Slow release magnesium composition and uses thereof

ABSTRACT

The present invention provides compositions that contain magnesium and threonate, or a threonate precursor molecule, formulated for extended or modified release to provide physiological concentrations over a desired time period. The extended release or modified release form is particularly useful in providing Mg to a subject while avoiding adverse side effects such as diarrhea.

RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.61/222,420, filed Jul. 1, 2009, which is incorporated by referenceherein in its entirety.

BACKGROUND OF THE INVENTION

Magnesium is the fourth most abundant mineral in the human body andplays multiple roles in maintaining good health. At the molecular level,magnesium is a cofactor for over 300 enzymes responsible for some of themost important biological activities in mammals, including humans. Inliving cells, magnesium is involved in the homeostasis of otherminerals, such as sodium, potassium and calcium, and the formation,transfer, storage and utilization of adenosine triphosphate (ATP), aprincipal source of energy in living cells. In the human body, magnesiumis involved in the maintenance of normal muscle and nerve function,heart rhythm, bone strength, and immune system health. Magnesium is alsoinvolved in the regulation of blood sugar levels and the promotion ofnormal blood pressure.

Magnesium deficit has been associated with several diseases, includinghypertension, atherosclerosis, arrhythmia, diabetes, and metabolicsyndromes. In addition, magnesium deficit accelerates cell-agingprocesses (Killilea D W, Ames B N. Magnesium deficiency acceleratescellular senescence in cultured human fibroblasts. Proc Natl Acad SciUSA. 2008 Apr. 15; 105:5768-73). Magnesium is also important for brainfunction. For example, magnesium deficit is implicated in attentiondeficit hyperactivity disorder (Kozielec T, Starobrat-Hermelin B. MagnesRes. 1997 June; 10:143-8; Mousain-Bosc M, Roche M, Polge A, Pradal-PratD, Rapin J, Bali J P. Magnes Res. 2006 March; 19:46-52), affectivedisorders (Murck H. Nutritional neuroscience. 2002 December; 5:375-89),Alzheimer's disease (Andrasi E, Pali N, Molnar Z, Kosel S. J AlzheimersDis. 2005 August; 7:273-84; Cilliler A E, Ozturk S, Ozbakir S.Gerontology. 2007 Nov. 8; 53:419-22; Lemke M R. Biol Psychiatry. 1995Mar. 1; 37:341-3), migraine (Ramadan N M, Halvorson H, Vande-Linde A,Levine S R, Helpern J A, Welch K M. Headache. 1989 October; 29:590-3;Facchinetti F, Sances G, Borella P, Genazzani A R, Nappi G. Magnesiumprophylaxis of menstrual migraine: effects on intracellular magnesium.Headache. 1991 May; 31:298-301), and Autism (Martineau J, Barthelemy C,Garreau B, Lelord G. Biol Psychiatry. 1985 May; 20:467-78; Pfeiffer S I,Norton J, Nelson L, Shott S. J Autism Dev Disord. 1995 October;25:481-93; Strambi M, Longini M, Hayek J, Berni S, Macucci F, ScalacciE, Vezzosi P., Biol Trace Elem Res. 2006 February; 109:97-104).

Recently, it has been found that elevation of extracellular magnesiumleads to a significant enhancement of synaptic plasticity and synapticdensity in cultured hippocampal neurons (Slutsky I, Sadeghpour S, Li B,Liu G. Neuron. 2004 Dec. 2; 44:835-49). The synaptic network is believedto be involved in organization of neural circuits during earlydevelopment and in learning and memory processes. Indeed, in patientswith Alzheimer's disease, there is a strong inverse correlation betweenthe number of synapses and the degree of cognitive impairment (Terry RD, Masliah E, Salmon D P, Butters N, DeTeresa R, Hill R, Hansen L A,Katzman R. Ann Neurol. 1991 October; 30:572-80; Selkoe D J. Science.2002 Oct. 25; 298:789-91). During normal aging, memory decline alsocorrelates with synaptic loss (Terry R D, Masliah E, Salmon D P, ButtersN, DeTeresa R, Hill R, Hansen L A, Katzman R. Ann Neurol. 1991 October;30:572-80). Interestingly, brain magnesium contents in AD patients(Andrasi E, Pali N, Molnar Z, Kosel S. J Alzheimers Dis. 2005 August;7:273-84; Cilliler A E, Ozturk S, Ozbakir S. Gerontology. 2007 Nov. 8;53:419-22) are lower than normal subjects. Elevation of brain magnesiummight be beneficial for prevention of synapse loss and amelioration ofmemory decline during aging and the pathological processes of AD.

Despite the important physiological role of magnesium, people may notconsume enough magnesium in their diets. In a national sample of theUnited States, the mean value of daily magnesium between the ages of20-30 is ˜300 mg for white and ˜250 mg for black males. This dailyintake declines, at ages above 70 years, to ˜200 mg as a result ofreduced food consumption. On the other hand, the recommended dailyallowance (RDA) for males is 420 mg/day. Therefore, it is likely thatthe majority of the American male population has magnesium deficit,particularly during aging. A similar degree of deficit also occurs inAmerican female population (Ford E S, Mokdad A H. J. Nutr. 2003September; 133:2879-82). Based on this study, most of the Americanpopulation needs to supplement their diet with an additional ˜200 mg/dayof magnesium. Interestingly, magnesium contained in food providesrelatively high absorption rate magnesium (˜50%), which may suggest that˜100 mg/day magnesium remains needed to be absorbed into the body. Ingeneral, most commercially available magnesium preparations have amagnesium absorption rate ≦˜40%. For example, magnesium oxide, which isperhaps the most widely used magnesium supplement, has a magnesiumabsorption rate of only about 4% (Firoz M, Graber M. Bioavailability ofUS commercial magnesium preparations. Magnes Res. 2001 December;14:257-62)). The present invention provides controlled release magnesiumcompositions for use as a magnesium dietary supplement.

SUMMARY OF THE INVENTION

To supply the population with sufficient magnesium, a very high dose ofmagnesium supplement is required to reach the recommended dailyallowance (RDA). For example, 4 grams of magnesium oxide would berequired as an oral supplement. A slow release magnesium compositionoffers several advantages. Slow release avoids high concentration ofmagnesium in the gastrointestinal (GI) tract. Unabsorbed magnesium inthe GI tract often leads to diarrhea. Slow release can avoidaccumulation of unabsorbed magnesium and reduce such adverse effects.The present invention discloses such dosage forms and methods of usethereof.

In one aspect, the present invention provides an oral dosage formcomprising magnesium (Mg) and threonate (T), wherein said threonatecomprises one or more of a threonate salt or a threonate precursor,wherein said oral dosage form has an in vitro dissolution profile in adissolution medium, and wherein said dissolution profile ranges betweenless than or equal to 5% in about 2 hours, less than 10% in about 4hours, less than 40% in about 6 hours, greater than or equal to 60% inabout 10 hours, and greater than or equal to 80% in about 12 hours asmeasured using a USP type II (paddle) dissolution system at 75 rpm, at atemperature of 37° C.

In some embodiments, the magnesium and threonate in said oral dose formis encapsulated in a tablet. In some embodiments, at least a portion ofsaid magnesium (Mg) and threonate (T) is complexed in a salt form ofMgT₂. In some embodiments, at least a portion of said magnesium (Mg) andthreonate (T) is complexed in a salt form of MgT₂ present in an amountequal to at least about 20 mg of Mg by weight. In other embodiments, amolar ratio between said threonate (T) and said magnesium (Mg) isgreater than or equal to about 0.1 to 2. In yet other embodiments, thethreonate precursor comprises a threonic acid, a threonate ester, or athreonate lactone. In still other embodiments, said magnesium (Mg) ispresent in an amount greater than about 1% by weight. In furtherembodiments, said magnesium (Mg) is present in an amount greater thanabout 5% by weight, or in an amount greater than about 7% by weight.

In some embodiments, said magnesium (Mg) is complexed with an anionselected from the group consisting of chloride, taurinate, lactate,gluconate, citrate, malate, succinate, sulfate, propionate, hydroxide,oxide, orotate, phosphate, borate, salicylate, carbonate, bromide,stearate, an amino acid, butyrate, aspartate, ascorbate, picolinate,pantothenate, nicotinate, benzoate, phytate, caseinate, palmitate,pyruvate, and threonate. In other embodiments, the oral dosage formfurther comprises a metal ion selected from the group consisting ofcalcium, potassium, sodium, chromium, iron, selenium, zinc, manganese,molybdenum, vanadium, and lithium. In some other embodiments, the oraldosage form further comprises one or more antioxidant selected from thegroup consisting of resveratrol, ellagic acid, quecertin, lipoic acidand vitamin C.

In some embodiments, said dissolution profile ranges between less than5% in about 2 hours, less than 10% in about 4 hours, less than 40% inabout 6 hours, greater than or equal to 60% in about 10 hours, andgreater than or equal to 80% in about 12 hours as measured using a USPtype II (paddle) dissolution system at 75 rpm, at a temperature of 37°C. In some embodiments, the dissolution profile is zero order.

In some embodiments, at least 75% of said magnesium (Mg) and threonate(T) in said oral dose form is provided in a controlled release dosageform. In some embodiments, at least 95% or more of said magnesium (Mg)and threonate (T) in said oral dose form is provided in a controlledrelease dosage form. In some embodiments, 100% of said magnesium (Mg)and threonate (T) in said oral dose form is provided in a controlledrelease dosage form.

In some embodiments, the dissolution medium is a saline solution. Insome embodiments, the oral dosage form further comprises a polymerbinder mixed with the magnesium (Mg) and threonate (T). In someembodiments, the polymer comprises polyvinylpyrrolidone. In someembodiments, the oral dosage form further comprises a pharmaceuticallyacceptable amount of magnesium stearate. In some embodiments, the oraldosage form further comprises of one or more of polyvinylpyrrolidone,polyvinyl acetate, or propylene glycol.

In another aspect, the present invention provides an oral dosage formcomprising between about 10 mg to 500 mg elemental magnesium (Mg),wherein said oral dosage form is a controlled release formulation, andwherein upon administering said oral dosage form to a Sprague-Dawley ratat a dosage of equal to or less than about 75 mg/kg/day yields anincidence of diarrhea of less than 20%. In some embodiments, theincidence of diarrhea is less than 20% when administered at a dosage ofequal to or less than about 75 mg/kg/day for at least about 3 days. Insome embodiments, the dosage form has a dissolution rate of magnesiumabout 40-80% within about 6 to 10 hours. In some embodiments, said oraldosage form provides for an incidence of diarrhea of less than 50% whenadministered at a dosage of equal to or less than about 130 mg/kg/day.

In another aspect, the present invention provides an oral dosage formcomprising magnesium (Mg) and threonate (T), wherein said threonatecomprises one or more of a threonate salt or a threonate precursor,wherein said oral dosage form is effective in increasing the life spanof a subject on a high calorie diet. In some embodiments, administeringsaid oral dosage form to a subject on a high calorie diet yields aprotective effect such that said subject's life span is comparable to anaverage life span of a subject having a median weight. In someembodiments, said oral dosage form is administered to a human subject ata dose between about 1 mg elemental magnesium/kg/day to about 16 mgelemental magnesium/kg/day. In some embodiments, the oral dosage formincreases survival rate by at least about 40% in subjects who are on ahigh calorie diet for at least about 60 weeks.

In another aspect, the present invention provides an oral dosage formcomprising magnesium (Mg) and threonate (T), wherein said threonatecomprises one or more of a threonate salt or a threonate precursor,wherein administering said oral dosage form to a subject providesprotection against adverse effects of a high calorie diet in saidsubject. The adverse effects can include but are not limited toartherosclerosis, heart disease, myocardial infarction, stroke,thromboembolism, metabolic syndrome, and diabetes. In some embodiments,said oral dosage form is administered to a human subject at a dosebetween about 1 mg elemental magnesium/kg/day to about 16 mg elementalmagnesium/kg/day. In some embodiments, the oral dosage form increasessurvival rate by at least about 40% in subjects who are on a highcalorie diet for at least about 60 weeks.

In another aspect, the present invention provides an oral dosage formcomprising magnesium (Mg) and threonate (T), wherein said threonatecomprises one or more of a threonate salt or a threonate precursor,wherein said oral dosage form is readily absorbed or retained uponadministering said oral dosage form to a subject at least about 50% ofsaid administered magnesium is absorbed in said subject, or that atleast about 30% of the magnesium administered to the subject is retainedover a period of at least two days when said oral dosage form isadministered at a dose of about 20 mg/kg/day or higher.

In some embodiments, the subject is a Sprague-Dawley rat. In someembodiments, more than about 60% of said administered magnesium isabsorbed in said subject. In some embodiments, more than about 40% ofsaid administered magnesium is retained over a period of at least twodays when said oral dosage form is administered at a dose of about 20mg/kg/day or higher. In some embodiments, the oral dosage form exhibitsa dose-proportional increase in absorbed magnesium when administered toa subject in an amount between about 20 mg/kg/day and about 80mg/kg/day.

In some embodiments, the oral dosage forms of the present inventioncomprise magnesium (Mg) and threonate (T), wherein said threonatecomprises one or more of a threonate salt or a threonate precursor, andwherein the oral dosage form when administered to the subject providesan increased concentration of magnesium in a cerebral spinal fluid ofthe subject, wherein said increased concentration of magnesium in saidcerebral spinal fluid of the subject ranges between about a 5% increaseto about a 10% increase after about 10 days administering said oraldosage form to said subject as compared to a baseline magnesiumconcentration in the absence of administering magnesium.

In another aspect, the present invention provides a method of treating acondition related to magnesium deficiency comprising administering to asubject in need thereof an oral dosage form disclosed herein. In someembodiments, the condition is selected from the group consisting of aneurological disorder, a cardiovascular disorder, and a metabolicdisorder.

In yet another aspect, the present invention provides a method ofelevating magnesium in a central nervous system of a subject in needthereof comprising administering to said subject an oral dosage formprovided by the invention.

In yet another aspect, the present invention provides a method ofmaintaining a high calorie diet without a substantial risk of highcalorie related adverse effect, comprising administering to a subject inneed thereof an oral dosage form provided by the invention.

In still another aspect, the present invention provides a method ofsupplementing magnesium in a subject in need thereof, comprisingadministering an oral dosage form provided by the invention to saidsubject at least once a day.

In yet still another aspect, the present invention provides a method ofsupplementing magnesium in a subject in need thereof, comprisingadministering an oral dosage form provided by the invention to saidsubject at least twice a day for a period of 1 month or longer.

The present invention also provides a method of making an oral dosageform as described above, comprising mixing a powder comprising magnesium(Mg) and threonate (T), both of which being present in a salt form, witha polymer in an amount sufficient to create particles comprising themagnesium (Mg), the threonate (T), and the polymer, wherein saidparticles are of a size sufficient to be retained by a 12 mesh sieve. Insome embodiments, the method further comprises filtering said particlesto remove un-bound threonate using the 12 mesh sieve; drying theparticles; adding a pharmaceutically acceptable amount of lubricant tosaid particles; compressing the particles into one or more pills of sizebetween about 100 mg and about 2000 mg; and coating said one or morepills with a polymer coating comprising one or more ofpolyvinylpyrrolidone, polyvinyl acetate, or propylene glycol.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the invention are set forth with particularity inthe appended claims. A better understanding of the features andadvantages of the present invention will be obtained by reference to thefollowing detailed description that sets forth illustrative embodiments,in which the principles of the invention are used, and the accompanyingdrawings of which:

FIG. 1 illustrates a plot of the incidence of diarrhea in rats provideddifferent magnesium preparations. The γ-axis is the incidence ofdiarrhea and the x-axis is the dosage of elemental magnesium per kg perday. The magnesium compounds were magnesium citrate (MgCitrate);magnesium chloride (MgCl₂); magnesium gluconate (MgG); magnesiumgluconate in milk (MgG+milk); and magnesium threonate (MgT).

FIG. 2 illustrates a series of plots showing the absorption,reabsorption and retention rate of different magnesium preparations. Thepreparations included magnesium chloride (MgCl₂); magnesium citrate(MgCitrate); magnesium gluconate (MgG); magnesium glycinate (MgGly); andmagnesium threonate (MgT). FIG. 2A illustrates the relationship betweenmagnesium (Mg) intake and the absorbed amount of magnesium for magnesiumthreonate (MgT) and MgCl₂. The absorption rate was estimated by linearregression. FIG. 2B illustrates the absorption rate of differentmagnesium preparations displayed as a percentage. FIG. 2C illustratesthe relationship between absorbed magnesium and magnesium excreted inthe urine. The excretion rate was estimated by linear regression. FIG.2D illustrates the excretion rate of different magnesium preparationsdisplayed as a percentage. FIG. 2E illustrates the relationship betweenmagnesium intake and its retention in the body. The retention rate wasestimated by linear regression. FIG. 2F illustrates the retention rateof different magnesium preparations displayed as a percentage.

FIG. 3 illustrates a plot of the elevation of magnesium concentration incerebrospinal fluid ([Mg²⁺]_(CSF)) following treatment with differentpreparations. The γ-axis shows the change in [Mg²⁺]_(CSF) and the x-axisrepresents time in days. The magnesium compounds were magnesium chloride(MgCl₂); magnesium gluconate in milk (MgG+milk); and magnesium threonate(MgT).

FIG. 4A illustrates survival curves for male mice with and withoutmagnesium threonate (MgT) supplementation. FIG. 4B illustrates survivalcurves of female mice with and without MgT supplementation.

FIG. 5A illustrates the body weight of mice fed a standard or highcalorie (HC) diet over time. FIG. 5B illustrates survival curves of miceunder standard or high calorie diet. Mice under high calorie diet haveshorter life span than the mice under standard diet. Mice under highcalorie diet plus MgT had life span similar to mice under standard diet.

FIG. 6A illustrates a controlled-release tablet comprising magnesiumthreonate. FIG. 6B illustrates the release profile of acontrolled-release tablet comprising magnesium threonate formulatedaccording to I.Example 6.

DETAILED DESCRIPTION OF THE INVENTION I. Controlled Release Oral DosageForms

The present invention provides compositions that contain magnesium andthreonate, or a threonate precursor molecule, formulated for extended ormodified release to provide a serum or plasma concentration over adesired time period that is high enough to be physiologically effectivebut at a rate low enough so as to avoid adverse events associated withhigh levels of magnesium. Adverse effects that would otherwise beassociated with high Mg content include diarrhea. Controlled release ofthe magnesium is desirable for reducing and delaying the peak plasmalevel while maintaining bioavailability. Physiologically effectivelevels are therefore achieved while minimizing side-effects that can beassociated with immediate release formulations. Furthermore, as a resultof the delay in the time to obtain peak serum or plasma level and theextended period of time at the therapeutically effective serum or plasmalevel, the dosage frequency is reduced to, for example, once or twicedaily dosage, thereby improving subject compliance and adherence. Forexample, side effects including diarrhea associated with theadministration of magnesium may be lessened in severity and frequencythrough the use of controlled-release formulations that increase thetime to maximum concentration in the body, thereby reducing the changein concentration of the magnesium over time. Reducing the concentrationchange also reduces the concentration of the active ingredient at itsmaximum time point and provides a more constant amount of magnesium tothe subject being treated over a given period of time, which can furtherenable increased dosages for appropriate indications.

Controlled release within the scope of this invention can be taken tomean any one of a number of extended release dosage forms. Non-limitingexamples of extended release dosage forms are described in Heaton et al.U.S. Patent Application Pub. No. 2005/0129762 and Edgren et al. U.S.Patent Application Pub. No. 2007/0128279, which are herein incorporatedby reference. Time-release formulations are known in the art, some ofwhich are described in Sawada et al. U.S. Patent Application Pub. No.2006/0292221, herein incorporated by reference. The following terms maybe considered to be substantially equivalent to controlled release forthe purposes of the present invention: modified release, continuousrelease, controlled release, delayed release, depot, gradual release,long-term release, programmed release, prolonged release, proportionaterelease, protracted release, repository, retard, slow release, spacedrelease, sustained release, time coat, timed release, delayed action,extended action, layered-time action, long acting, prolonged action,repeated action, slowing acting, sustained action, sustained-actionmedications, and extended release. Further discussions of these termsmay be found in Lesczek Krowczynski, Extended-Release Dosage Forms, 1987(CRC Press, Inc.). The various controlled release technologies cover avery broad spectrum of dosage forms. Controlled release technologiesinclude, but are not limited to, physical systems and chemical systems.

A composition, kit, and/or a method described herein may be useful forpurposes described herein, such as maintaining, enhancing, and/orimproving health, nutrition, and/or another condition of a subject,and/or cognitive, learning, and/or memory function, for example, such asmagnesium deficiency, mild cognitive impairment (MCI), Alzheimer'sdisease (AD), attention deficit hyperactivity disorder (ADHD),amyotrophic lateral sclerosis (ALS) or Lou Gehrig's disease, Parkinson'sdisease, Schizophrenia, diabetes, migraine, anxiety, mood, andhypertension, merely by way of example.

The compositions of the present invention can be formulated in slowrelease or sustained release forms, whereby a relatively consistentlevel of the magnesium threonate is provided over an extended period. Insome embodiments, a magnesium counter-ion composition and/or othertherapeutic agents may be administered jointly or separately by using acontrolled release dosage form. In one embodiment, the present inventionprovides an oral dosage form comprising magnesium (Mg) and threonate(T), wherein said threonate comprises one or more of a threonate salt ora threonate precursor, wherein said oral dosage form has an in vitrodissolution profile in a dissolution medium, and wherein saiddissolution profile ranges between less than or equal to 5% in about 2hours, less than 10% in about 4 hours, less than 40% in about 6 hours,greater than or equal to 60% in about 10 hours, and greater than orequal to 80% in about 12 hours as measured using a USP type II (paddle)dissolution system at 75 rpm, at a temperature of 37° C. In anotherembodiment, the dissolution profile ranges between less than 5% in about2 hours, less than 10% in about 4 hours, less than 40% in about 6 hours,greater than or equal to 60% in about 10 hours, and greater than orequal to 80% in about 12 hours as measured using a USP type II (paddle)dissolution system at 75 rpm, at a temperature of 37° C. In anotherembodiment, the dissolution profile ranges between less than 5% in about2 hours, less than 10% in about 4 hours, less than 40% in about 6 hours,greater than or equal to 60% in about 10 hours, and greater than orequal to 80% in about 12 hours as measured using a USP type II (paddle)dissolution system at 75 rpm, at a temperature of 37° C. In someembodiments of the oral dosage forms as described herein, said magnesiumand threonate is encapsulated in a tablet.

In some embodiments, at least 75% of said magnesium (Mg) and threonate(T) in the controlled release oral dosage forms of the present inventionis provided in a controlled release dosage form. In some embodiments, atleast 95% of said magnesium (Mg) and threonate (T) in the controlledrelease oral dosage forms is provided in a controlled release dosageform. In some embodiments, 100% of said magnesium (Mg) and threonate (T)in said oral dose form is provided in a controlled release dosage form.In some embodiments, the dissolution medium is a saline solution. Insome embodiments, the dissolution profile is zero order, i.e., the rateof dissolution is independent of concentration.

A release profile, i.e., the extent of release of the magnesium over adesired time, can be conveniently determined for a given time bymeasuring the release under controlled conditions, e.g., using a USPdissolution apparatus. Preferred release profiles are those which slowthe rate of uptake of the magnesium into the blood stream whileproviding therapeutically effective levels of the magnesium. Accordingto standardized dissolution testing guidelines for controlled release(“CR”) profiles, dissolution of the active ingredient is measured atgiven intervals over a period of time. A minimum of three time points isrecommended and generally cover early, middle and late stages of thedissolution profile. The last measurement should be no earlier than thetime point where at least 80% of the active ingredient is dissolved(Guidance for Industry, “Extended Release Oral Dosage Forms:Development, Evaluation, and Application of In Vitro/In VivoCorrelations”, Food and Drug Administration, CDER, September 1997, Page17). Adequate sampling is important: for example, at 1, 2 and 4 hoursand every two hours thereafter until 80% of the active ingredient isreleased (Guidance for Industry, SUPAC-MR: Modified Release Solid OralDosage Forms,” Food and Drug Administration, CDER, September 1997, Page6). The preferred dissolution apparatus is USP apparatus I (basket) orII (paddle), used at recognized rotation speeds, e.g., 100 rpm for thebasket and 50-75 rpm for the paddle (Guidance for Industry, “ExtendedRelease Oral Dosage Forms: Development, Evaluation, and Application ofIn Vitro/In Vivo Correlations”, Food and Drug Administration, CDER,September 1997, Page 4). Controlled release dosage forms permit therelease of the active ingredient over an extended period of time. On theother hand, materials which dissolve at least 80% in the first 30 to 60minutes in solution qualify as immediate release (“IR”) profiles.(“Dissolution Testing of Immediate Release Solid Oral Dosage Forms”,issued August 1997, Section IV-A). Therefore, immediate release solidoral dosage forms permit the release of most, or all, of the activeingredient over a short period of time, such as 60 minutes or less.

The subject composition may comprise an active ingredient includingmagnesium, threonate, or a threonate precursor. In one embodiment, thesubject composition comprises a magnesium counter ion, as illustrated inthe formula provided below:

Such a composition may be prophylactically and/or therapeuticallysuitable or beneficial. Threonate is a natural metabolic product ofvitamin C or ascorbic acid that may be associated with non-toxicity inanimals (Thomas et al., Food Chem. 17, 79-83 (1985)) and biologicalbenefit, such as the promotion of vitamin C uptake, in animals(Verlangieri et al., Life Sci. 48:2275-2281 (1991)).

In some embodiments, the threonate comprises threonate and/or threonateprecursor molecules. Threonate can be in the form of a salt. The term“threonate precursor” generally means a precursor molecule that can bereadily converted to threonate when the composition is dissolved in anaqueous media or ingested as a result of ionization or hydrolysis withor without the aid of an enzyme. The precursor can be a threonic acid,an ester derivative of threonic acid or threonate, or a lactonizedthreonic acid. Generally, threonate as used in the present inventionrefers to L-threonate. For example, an L-threonate precursor may beL-threonic acid, an ester derivative of L-threonic acid or L-threonate,or a lactonized L-threonic acid. In some embodiments, D-threonate orprecursors thereof are used in the present invention.

In some embodiments, at least a portion of said magnesium (Mg) andthreonate (T) is complexed in a salt form of MgT₂. In some embodiments,at least a portion of said magnesium (Mg) and threonate (T) is complexedin a salt form of MgT₂ present in an amount equal to at least about 20mg of Mg by weight. In some embodiments, the molar ratio between saidthreonate (T) and said magnesium (Mg) is greater than or equal to about0.1 to 2. In some embodiments, the magnesium (Mg) is present in anamount greater than about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%,12%, 13%, 14%, or 15% by weight. In some embodiments, the magnesium (Mg)is present in an amount greater than about 1%, 5%, or greater than about7% by weight.

The compositions of the present invention generally comprise asufficient amount (as defined further below) of magnesium ion(hereafter, “magnesium”) and threonate or a threonate precursormolecule, wherein either magnesium or threonate may or may not be in theform of magnesium threonate in said compositions. When magnesium is notin the form of magnesium threonate but another magnesium salt, the othermagnesium salt may be any suitable inorganic or organic magnesium salt.Herein, the term “suitable,” generally means that the anion of themagnesium salt is nontoxic. Examples of suitable salts include, but arenot limited to, magnesium salts of chloride, sulfate, oxide, acetate,lactate, citrate, malate, D-threonate, gluconate, taurinate, andpidolate. Similarly, when threonate is not in the form of magnesiumthreonate, it may be in the form of another threonate salt comprisinganother nontoxic cation. Suitable nontoxic cations include potassium,sodium, calcium and ammonium. In some embodiments, the suitable nontoxiccation is potassium. Generally, the present invention uses the term“threonate” to comprise threonate and precursors thereof, includingsalts, acids, esters and lactones, by way of example.

In addition to magnesium threonate, the compositions may comprise atleast one magnesium-comprising component (MCC) or also used herein asmagnesium-counter ion compound. Examples of an MCC include a magnesiumsalt of an amino acid, magnesium acetate, magnesium ascorbate, magnesiumcitrate, magnesium gluconate, magnesium lactate, magnesium malate,magnesium pyrrolidone carboxylate, and magnesium taurate. Alternatesalts of the compositions disclosed herein include, but are not limitedto, acid addition salts, such as those made with hydrochloric,methylsulfonic, hydrobromic, hydroiodic, perchloric, sulfuric, nitric,phosphoric, acetic, propionic, glycolic, lactic pyruvic, malonic,succinic, maleic, fumaric, maleic, tartaric, citric, benzoic, carboniccinnamic, mandelic, methanesulfonic, ethanesulfonic,hydroxyethanesulfonic, benezenesulfonic, p-toluene sulfonic,cyclohexanesulfamic, salicyclic, p-aminosalicylic, 2-phenoxybenzoic, and2-acetoxybenzoic acid. The term “salts” can also include addition saltsof free acids or free bases. All of these salts (or other similar salts)may be prepared by conventional means. All such salts are acceptableprovided that they are non-toxic and do not substantially interfere withthe desired pharmacological activity.

An MCC composition of the present invention may comprise at least onecomponent of non-acidified milk sufficient to enhance bioavailability ofelemental magnesium associated with the MCC. Examples of such acomponent include lactose, a fatty acid or milk fat, and/or anotherorganic component thereof, for example, sufficient for such enhancement.A mass ratio of the amount of elemental magnesium associated with the atleast one MCC and the amount of the component may be from about 1 toabout 5 to about 1 to about 3000. Such a composition may be suitable fororal administration to a subject.

Magnesium threonate is a highly bioavailable form of a magnesiumcounter-ion composition. However, the in vivo accessibility of thismagnesium threonate may be provided in multiple ways. In someembodiments, a subject ingests magnesium threonate. In otherembodiments, magnesium may be taken with other supplements which resultin an in vivo reconstitution of magnesium-counter ion composition.Without being bound by theory, the threonate may function to promotecellular uptake of magnesium in any form and may also enhance deliveryto the brain and central nervous system. Thus, in some embodiments,magnesium may be given uncomplexed with threonate and threonate isprovided to the same subject to enhance absorption. For example,magnesium gluconate and potassium threonate may be taken nearconcurrently to result in an in vivo reconstitution of magnesiumthreonate and/or enhance magnesium uptake and/or delivery of magnesiumto the brain. In another example, certain counter ions may be metabolicproducts of other substances. For example, vitamin C is metabolized intothe threonate ion in humans; therefore, ingestion of magnesium in a formwhich can be taken up by the body and vitamin C may result in thereconstitution of magnesium threonate in the body. Another example of asubstance which is metabolized to threonate in humans is ascorbate.Thus, in some embodiments of the present invention, magnesium ascorbatemay be provided to a subject and this substance would be metabolized tomagnesium and threonate in vivo. One of skill in the art will recognizethat these examples are provided by way of illustration only and thatother combinations of magnesium compounds and secondary compounds mayresult in the reconstitution of a magnesium-counter-ion composition invivo.

A magnesium-counter ion composition comprising more than onemagnesium-counter ion compound may be suitable, beneficial or desirablerelative to a magnesium-counter ion composition comprising a singlemagnesium-counter ion compound. A combination of more than onemagnesium-counter ion compound may be suitable, beneficial or desirablein terms of any number of features or factors, such as magnesiumcontent, solubility, palatability, magnesium bioavailability, biologicalacceptability, and/or the like, for example. A combination of more thanone magnesium-counter ion compound may be suitable, beneficial ordesirable in terms of palatability. A combination of more than onemagnesium-counter ion compound may be suitable, beneficial or desirablein terms of maintaining and/or enhancing an attribute or attributes of amagnesium-counter ion compound or several magnesium-counter ioncompounds.

The relative amount of threonate-to-magnesium molar ratio can beadjusted for various formulations. Generally, the molar ratio ofthreonate-to-magnesium is ≧˜1/5. Because each MgT contains 2 threonate,this means at least 10% of Mg is from MgT. The other 90% may be fromMgCl₂ or other Mg salt. In some embodiments, the threonate-to-magnesiummolar ratio is ≧˜2/7. For example, this ratio corresponds to anutraceutical formulation comprising about 50 mg Mg in the form of MgTand about 300 mg of Mg in the form of MgCl₂ or other Mg salt in a 350 mgMg recommended daily allowance (RDA). In other embodiments, thethreonate-to-magnesium molar ratio is about 2. In some embodiments, allthreonate in said composition is in the form of magnesium threonate,which is the effective component of said compositions. When saidmagnesium and threonate are each part of separate compounds in thecompositions and said compositions are dissolved or orally ingested, atleast part of the magnesium and part of threonate will form magnesiumthreonate in situ as a result of ionic exchange reactions. In someembodiments, all of the magnesium and all of the threonate are from thesame magnesium threonate compound, e.g., to minimize the mass of thecomposition. In some embodiments, when the threonate to magnesium molarratio is less than 2, a portion of the magnesium comes from anothermagnesium compound. In some embodiments, the other magnesium compound isselected from magnesium chloride, magnesium taurinate, magnesiumlactate, magnesium gluconate, magnesium citrate and magnesium malate.

The exact amount of magnesium used in a given dosage form of the presentinvention depends on the physical form of said composition. According toone embodiment, the invention provides a solid or semi-solid compositioncomprising at least 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% or moreelemental magnesium by weight. According to one embodiment, the solid orsemi-solid composition is a pill comprising at least 20 mg elementalmagnesium, or at least 50 mg of elemental magnesium, or at least 80 mgof elemental magnesium.

The controlled release compositions of the present invention have anumber of advantages. For example, the invention can also enable areduction in the dosing frequency. For example, the controlled releasecompositions of the present invention may be employed to administer themagnesium at a lower frequency than it would be with an immediaterelease formulation (i.e., once a day (q.d.) versus twice a day (b.i.d)or three times a day (t.i.d)), hence improving subject compliance andcaregiver convenience. In some embodiments, the compositions describedherein are administered even less frequently, e.g. every 2 days, every 3days, every week, or every month. These compositions are particularlyuseful as they provide the magnesium at a biologically effective amountfrom the onset of administration further improving compliance andadherence and enable the achievement of an effective steady-stateconcentration of the magnesium in a shorter period of time. Furthermore,the compositions of the present invention, by virtue of their design,allow for higher doses of magnesium to be safely administered, againincreasing the utility of these agents for a variety of indications.

Using the controlled release dosage forms provided by the presentinvention, the magnesium is released into a subject sample at a slowerrate than observed for an immediate release (IR) formulation of the samequantity of magnesium. In some embodiments, the rate of change in thebiological sample measured as the change in concentration over a definedtime period from administration to maximum concentration for ancontrolled release formulation is less than about 80%, 70%, 60%, 50%,40%, 30%, 20%, or 10% of the rate of the IR formulation. Furthermore, insome embodiments, the rate of change in concentration over time is lessthan about 80%, 70%, 60%, 50%, 40%, 30%, 20%, or 10% of the rate for theIR formulation. In some embodiments, the rate of change in concentrationover time is less than about 5% of the rate for the IR formulation.

In some embodiments, the rate of change of concentration over time isreduced by increasing the time to maximum concentration in a relativelyproportional manner. For example, a two-fold increase in the time tomaximum concentration may reduce the rate of change in concentration byapproximately a factor of 2. As a result, the magnesium may be providedso that it reaches its maximum concentration at a rate that issignificantly reduced over an immediate release (IR) dosage form. Thecompositions of the present invention may be formulated to provide ashift in maximum concentration by 24 hours, 16 hours, 8 hours, 4 hours,2 hours, or at least 1 hour. The associated reduction in rate of changein concentration may be by a factor of about 0.05, 0.10, 0.25, 0.5 or atleast 0.8. In certain embodiments, this is accomplished by releasingless than about 30%, 50%, 75%, 90%, or 95% of the magnesium into thecirculation within one hour of such administration.

Optionally, the controlled release formulations exhibit plasmaconcentration curves having initial (e.g., from 2 hours afteradministration to 4 hours after administration) slopes less than 75%,50%, 40%, 30%, 20% or 10% of those for an IR formulation of the samedosage of the same magnesium. The precise slope for a given individualwill vary according to the magnesium threonate composition, the quantitydelivered, or other factors, including, for example, whether the patienthas eaten or not. For other doses, e.g., those mentioned above, theslopes vary directly in relationship to dose.

Using the sustained release formulations or administration methodsdescribed herein, the magnesium reaches a therapeutically effectivesteady state plasma concentration in a subject within the course of thefirst 3, 5, 7, 9, 10, 12, 15, or 20 days of administration. For example,the formulations described herein, when administered at a substantiallyconstant daily dose, e.g., at a dose ranging between 50 mg and 1000 mg,preferably between 100 mg and 800 mg, and more preferably between 200 mgand 700 mg per day of elemental Mg, may reach a steady state plasmaconcentration in approximately 70%, 60%, 50%, 40%, 30%, or less of thetime required to reach such plasma concentration when using a doseescalating regimen.

In some embodiments, the rate of release of the magnesium from thepresent invention as measured in dissolution studies is less than about80%, 70%, 60% 50%, 40%, 30%, 20%, or 10% of the rate for an IRformulation of the same magnesium over the first 1, 2, 4, 6, 8, 10, or12 hours. In some embodiments, the rate of release of the magnesium fromthe present invention as measured in dissolution studies is less thanabout 80%, 70%, 60% 50%, 40%, 30%, 20%, or 10% of the rate for an IRformulation of the same magnesium over the first 2-4 hours. In someembodiments, the rate of release of the magnesium from the presentinvention as measured in dissolution studies is less than about 5% ofthe rate for an IR formulation of the same magnesium over the first 2-4hours.

The controlled release dosage forms provided by the present inventioncan adopt a variety of formats. In some embodiments, the supplementcomposition of the present invention is administered in an oral dosageform, including liquid dosage forms (e.g., a suspension or slurry), andoral solid dosage forms (e.g., a tablet or bulk powder). In someembodiments, the dosage form is provided as a tablet. As used herein theterm “tablet” refers generally to tablets, caplets, capsules, includingsoft gelatin capsules, and lozenges. The average tablet size for roundtablets is preferably about 10 mg to 150 mg elemental Mg and forcapsule-shaped tablets about 20 mg to 200 mg elemental Mg. Controlledrelease tablet generally fall into one of three categories: matrix,reservoir and osmotic systems. Although any of the three systems issuitable for the invention, the latter two systems have more optimalcapacity for encapsulating a relatively large mass as may be desirablefor the invention. In some embodiments, the slow-release tablet is basedon a reservoir system, wherein the magnesium- and threonate-containingcore is encapsulated by a porous membrane coating which, upon hydration,permits magnesium threonate to diffuse through. The effective dailydosage for human use can be about 50 to 1000 mg of magnesium, whichcorresponds to 606 to 12119 mg of magnesium threonate. The mass rangewill vary if magnesium and threonate are from compound sources otherthan magnesium threonate. Because the combined mass of the effectiveingredients is generally in gram quantity, an efficient delivery systemcan provide optimal results.

An example of controlled release tablet and its release profile areshown in FIG. 6, wherein the tablet comprises, in the core, magnesiumthreonate as magnesium composition, polyvinylpyrrolidone (PVP) asbinder, magnesium stearate as lubricant and, in the coating,polyvinylacetate (SR30D) as matrix former, PVP as pore former, talcpowder and TiO₂ as inert powders, propylene glycol as plasticizer and alake dye. See I.Example 6 and Table 1. The tablet according to the aboveformulation exhibits a zero order release profile over a 24 hour period.

The present invention further provides methods of making oral dosageforms as disclosed herein. Tablets are made by methods known in the artand may further comprise suitable binders, lubricants, diluents,disintegrating agents, colorants, flavoring agents, flow-inducingagents, melting agents, many varieties of which are known in the art.The oral dosage forms of the present invention may, optionally, have afilm coating to protect the components of the magnesium-counter ionsupplement composition from one or more of moisture, oxygen and light orto mask any undesirable taste or appearance. Suitable coating agentsinclude, for example, cellulose, hydroxypropylmethyl cellulose. In someembodiments, the oral dosage form comprises a plurality of beadsencapsulated in a capsule. Such format can be used as a sustainedrelease formulation. Other forms of tablets can also be formulated insustained release format. Methods of making sustained release tabletsare known in the art, e.g., see U.S. Patent Publications 2006/051416 and2007/0065512, or other references disclosed herein.

In some embodiments, oral dosage form according to the present inventionare made by mixing a powder comprising magnesium (Mg) and threonate (T),both of which can be present in a salt form, with a polymer in an amountsufficient to create particles comprising the magnesium (Mg), thethreonate (T), and the polymer, wherein said particles are of a sizesufficient to be retained by a 12 mesh sieve. In some embodiments, themethod further comprising: filtering said particles to remove unboundthreonate using the 12 mesh sieve; drying the particles; adding anacceptable amount of lubricant to said particles; compressing theparticles into one or more pills of total size between about 100 mg andabout 2000 mg and coating said one or more pills with a polymer coatingcomprising one or more of polyvinylpyrrolidone, polyvinyl acetate, andpropylene glycol. In some embodiments, the pills are made with anelemental magnesium content of from about 10 mg to about 200 mg. In someembodiments, one or more forms of threonate contained within the dosageform comprises a threonate salt of a threonate precursor molecule asdescribed herein. For example, a precursor may comprise threonic acid, athreonate ester, or a threonate lactone.

In some embodiments, the compositions described herein are preparedusing formulations as described in U.S. Pat. No. 4,606,909, entitled“Pharmaceutical multiple-units formulation.” This reference describes acontrolled release multiple unit formulation in which a multiplicity ofindividually coated or microencapsulated units are made available upondisintegration of the formulation (e.g., pill or tablet) in the stomachof the subject (see, for example, column 3, line 26 through column 5,line 10 and column 6, line 29 through column 9, line 16). Each of theseindividually coated or microencapsulated units containscross-sectionally substantially homogenous cores containing particles ofa sparingly soluble active substance, the cores being coated with acoating that is substantially resistant to gastric conditions but whichis erodable under the conditions prevailing in the gastrointestinaltract.

In some embodiments, the composition of the invention are formulatedusing the methods disclosed in U.S. Pat. No. 4,769,027, entitled“Delivery system,” for example. Accordingly, extended releaseformulations of physiologically acceptable material (e.g., sugar/starch,salts, and waxes) may be coated with a water permeable polymeric matrixcontaining magnesium and next overcoated with a water-permeable filmcontaining dispersed within it a water soluble particulate pore formingmaterial.

In some embodiments, the magnesium composition is prepared as describedin U.S. Pat. No. 4,897,268, entitled “Drug delivery system and method ofmaking the same,” for example, involving a biocompatible, biodegradablemicrocapsule delivery system. Thus, the magnesium may be formulated as acomposition containing a blend of free-flowing spherical particlesobtained by individually microencapsulating quantities of magnesium, forexample, in different copolymer excipients which biodegrade at differentrates, therefore releasing magnesium into the circulation at apredetermined rates. A quantity of these particles may be of such acopolymer excipient that the core active ingredient is released quicklyafter administration, and thereby delivers the active ingredient for aninitial period. A second quantity of the particles is of such typeexcipient that delivery of the encapsulated ingredient begins as thefirst quantity's delivery begins to decline. A third quantity ofingredient may be encapsulated with a still different excipient whichresults in delivery beginning as the delivery of the second quantitybeings to decline. The rate of delivery may be altered, for example, byvarying the lactide/glycolide ratio in a poly(D,L-lactide-co-glycolide)encapsulation. Other polymers that may be used include polyacetalpolymers, polyorthoesters, polyesteramides, polycaprolactone andcopolymers thereof, polycarbonates, polyhydroxybuterate and copolymersthereof, polymaleamides, copolyaxalates and polysaccharides.

In some embodiments, the composition of the present invention areprepared as described in U.S. Pat. No. 5,395,626, which features amultilayered controlled release dosage form. The dosage form contains aplurality of coated particles wherein each has multiple layers about acore containing magnesium whereby the magnesium containing core and atleast one other layer containing an active ingredient is overcoated witha controlled release barrier layer therefore providing at least twocontrolled releasing layers of a water soluble composition from themultilayered coated particle.

In some embodiments, the magnesium and threonate is prepared using theOROS® technology, described for example, in U.S. Pat. No. 6,919,373entitled “Methods and devices for providing prolonged drug therapy;”U.S. Pat. No. 6,923,800, entitled “Osmotic delivery system, osmoticdelivery system semipermeable body assembly, and method for controllingdelivery rate of beneficial agents from osmotic delivery systems;” U.S.Pat. No. 6,929,803 entitled “Conversion of liquid filled gelatincapsules into controlled release systems by multiple coatings;” and U.S.Pat. No. 6,939,556 entitled “Minimally compliant, volume efficientpiston for osmotic drug delivery systems;” all of which are herebyincorporated by reference. This technology employs osmosis to provideprecise, controlled delivery for up to 24 hours and can be used with arange of compounds, including those that are poorly soluble. OROS®technology can be used to deliver high doses meeting high loadingrequirements. By targeting specific areas of the gastrointestinal tract,OROS® technology may provide more efficient absorption and enhancedbioavailability of the active ingredient. The osmotic driving force ofOROS® and protection of the active ingredient until the time of releaseeliminate the variability of absorption and metabolism sometimes causedby gastric pH and motility.

Formulations for continuous long-term delivery are further provided in,e.g., U.S. Pat. No. 6,797,283, entitled “Gastric retention dosage formhaving multiple layers;” U.S. Pat. No. 6,764,697, entitled “System fordelaying drug delivery up to seven hours;” and U.S. Pat. No. 6,635,268,entitled “Sustained delivery of an active agent using an implantablesystem;” all of which are incorporated herein by reference.

In some embodiments, the controlled release dosage forms of the presentinvention comprise a plurality of beads, wherein each bead includes acore having a diameter from about 1 μm to about 1000 μm and the coreincludes an active ingredient comprising magnesium or a salt thereof inthe range of about 15 to about 350 mg Mg/g of the dosage form, whereinthe dosage forms include less than about 2.5% adduct and has adissolution rate of the active ingredient of more than about 80% withinabout the first 60 minutes following entry of the dosage forms into ause environment. In some embodiments, the dissolution rate is more thanabout 80% within 30 minutes.

In some embodiments, each bead includes a core and an active ingredientcomprising magnesium. A suitable bead form of magnesium may comprisemagnesium and threonate admixed with soluble components, e.g., sugars(e.g., sucrose, mannitol, etc.), polymers (e.g., polyethylene glycol,hydroxypropyl cellulose, hydroxypropyl methyl cellulose, etc.),surfactants (sodium lauryl sulphate, chremophor, tweens, spans,pluronics, and the like), insoluble glidant components (microcrystallinecellulose, calcium phosphate, talc, fumed silica, and the like), coatingmaterial (examples of suitable coating materials are polyethyleneglycol, hydroxypropyl methyl cellulose, wax, fatty acids, etc.),dispersions in suitable material (examples are wax, polymers,physiologically acceptable oils, soluble agents, etc.) or combinationsof the above.

According to some embodiments, the core includes sugar spheres(nonpareil seeds), microcrystalline cellulose, or mannitol. In someembodiments, the core is a sugar sphere, USP (Paulaur Cranbury, N.J.).In some embodiments, the particle size of the core ranges from about 1μm to about 1000 μm. In some embodiment, the particle size of the coreranges from about 300 μm to about 900 μm. In some embodiment, theparticle size of the core ranges from about 450 μm to about 825 μm. Inexemplary embodiments, the core may be coated to avoid interactionbetween the core and the active ingredient. For example, suitablecoating materials include, but are not limited to, polyethylene glycol,hydroxypropyl methyl cellulose, wax, fatty acids, etc.

In one embodiment, the spheres comprise a portion of the dosage formranging from about 50 mg/g to about 500 mg/g, preferably from about 60mg elemental magnesium per g of oral dosage form (i.e., 60 mg Mg/g), toabout 100 mg elemental magnesium per g of oral dosage form (i.e., 100 mgMg/g). The fraction of the bead will depend on the amount of additionalconstituents, if any, used in the dosage form.

The core can be coated with magnesium, e.g., magnesium threonate. In oneembodiment, magnesium threonate is present in amounts from about 150mg/g (or 12.4 mg Mg/g) to about 950 mg/g (or 78.4 mg Mg/g), preferablyfrom about 500 to 900 mg/g (or 41.2 to 74.3 mg Mg/g) based on the weightof the entire IR bead. In other embodiments, magnesium is present inamounts from about 15 to 300 mg/g, preferably from about 25 to about 250mg/g.

In one embodiment, magnesium threonate is added to a mixture of a binderand a glidant prior to coating the core. The glidant may be selectedfrom, but is not limited to, microcrystalline cellulose, calciumphosphate, talc, and fumed silica. Glidants may be used in amountsranging from 1.5 mg/g to about 35 mg/g. In some embodiments, glidantsrange from about 1.5 mg/g to about 30 mg/g. In some embodiments,glidants range from about 2.5 mg/g to about 25 mg/g. In anotherembodiment, the range of glidant is from about 5 mg/g to about 30 mg/g.

The binder may be selected from, but is not limited to, povidone (PVP),hydroxypropyl methylcellulose (HPMC, Opadry), hydroxypropyl cellulose(HPC), or combinations thereof. In an embodiment where the binder isHPMC, the binder is present in an amount ranging from about 15 mg/g toabout 30 mg/g, preferably from about 15 mg/g to about 25 mg/g. Inanother embodiment, where the binder is povidone, the binder is presentin an amount of from about 1.5 mg/g to about 35 mg/g, preferably fromabout 5 mg/g to about 30 mg/g.

The mixture of active ingredient and binder/water/glidant may beprepared by mixing, e.g., with a stirrer, for at least 15 minutes, forat least 30 minutes, or for at least one hour. The components may alsobe combined by methods including blending, mixing, dissolution andevaporation, or by using suspensions.

The active ingredient/binder/inactives mixture may be deposited on acore, wet massed and extruded, granulated, or spray dried. In oneembodiment, sugar spheres are prewarmed to a temperature ranging fromabout 40° C. to about 55° C. prior to application of the mixture. Thecore may be optionally coated with from about 2% w/w to about 10% w/wseal coating prior to applying the active layer. The seal coating may beany applicable coating which can separate any active ingredients fromthe core, for example, polymer coatings such as Eudragit®, HPMC, HPC, orcombinations thereof. For this reason also, dissolution stability (i.e.,maintenance of dissolution profile after exposure to elevatedtemperatures) is important for the compositions of the presentinvention.

In one embodiment, the sugar sphere are coated with a fluidized bedcoater known in the art, for example, a Glatt Powder Coater andGranulator, GPCG3 (Ramsey, N.Y.). One skilled in coating conditions suchas air velocity, spray rate, and atomization pressure are typicallycontrolled as is appreciated by and known to those skilled in the art.The temperature range of the product may range from about 43° C. toabout 51° C. The air velocity may range from about 5 to about 9 m/s. Thespray rate ranges from about 9 to about 42 gm/min. The atomizationpressure can range from about 1.5 to about 2.0 bar. The beads are thendried in the fluidized bed of the coating apparatus at a temperature ofabout 45° C. to about 50° C. for at least 5 minutes. In someembodiments, the beads are dried for at least 15 minutes, or for atleast 30 minutes. One skilled in the art will recognize that manyalternate operating conditions and various types of equipment can alsobe used.

Once the IR beads are formed as cores containing magnesium threonate asprovided herein, the beads may be optionally additionally coated with aseal coating. The seal coating may be a polymer or a combination ofpolymers that can be designed to be pH dependent or independent. In apreferred embodiment, the polymer for the seal coating is selected from,but are not limited to HPMC (Opadry®, Colorcon, Pa.), HPC, Eudragit® RL,Eudragit® E100, Eudragit® E 12.5, Eudragit®, E PO, Eudragit® NE (e.g.,NE 30D or NE 40D) and combinations of two or more of the foregoing.These polymers are insoluble in aqueous media but display pH-independentswelling on contact with aqueous fluids. In another embodiment, the IRbeads are coated with pH-dependent polymers, soluble at a pH preferablyabove 5. In the IR bead formulations, the seal coating polymer ispresent in amounts ranging from about 0% w/w to about 40% w/w,preferably from about 0% w/w to about 10% w/w, more preferably fromabout 0% w/w to about 3% w/w.

Alternatively the IR cores may be coated with a rapidly disintegratingor dissolving coat for aesthetic, handling, or stability purposes.Suitable materials are polyvinylpyrrolidone, hydroxypropyl cellulose,hydroxypropyl methyl cellulose, polyethylene glycol, polymethacrylatescontaining free amino groups, each may be with or without plasticizers,and with or without an antitack agent or filler. An addition of about 3%of the weight of the core as coating material is generally regarded asproviding a continuous coat for this size range. The over coating may bea polymer selected from, but are not limited to HPMC (Opadry®, Colorcon,Pa.), HPC, Eudragit® RL, Eudragit® E100, Eudragit® E 12.5, Eudragit® EPO, Eudragit® NE and mixtures thereof.

Dissolution of the active agent, e.g., magnesium threonate, from thebeads can occur by the penetration of the bulk medium and diffusionacross the polymer layer, which are in turn controlled by thepermeability and swelling properties of the polymer. In someembodiments, the modified release beads have near bioequivalent AUC(area under the curve, a measure of bioavailability) as compared to animmediate release tablet dosage form, and a reduced maximum plasmaconcentration of at least 25% relative to the immediate release tablet.The modified release bead demonstrates good tolerability and can beadministered over a wide range of dosages. In some embodiments, themaximum plasma concentration is less than about 85% of the immediaterelease tablets when administered as a single dose. In some embodiments,the AUC is within 75% to 130% of the immediate release tabletsadministered as a single dose. This range is considered equivalent withrespect to overall systemic exposure.

All of the beads from the controlled release formulation need notrelease immediately. This can prevent dose dumping and to reduce adverseevents. In some embodiments, the average time to reach maximum plasmaconcentration ranges from between about 5 to about 48 hours, or fromabout 5 to about 36 hours. In some embodiments, the beads have an invitro release rate of more than about 70% to about 80% in about 4 toabout 12 hours. In some embodiments, the formulations have a releaserate of about 30% to about 60% in about 2 to about 6 hours. In someembodiments, the formulations have a release rate of about 10% to about50%, or about 10% to 35% within the first hour following entry into ause environment followed by extended release.

In other embodiments, the present invention provides a composite dosageform comprising an immediate release (IR) component and a controlledrelease (CR) component, wherein the immediate release componentcomprises a first plurality of beads, each bead comprising a firstactive ingredient comprising magnesium or a salt thereof in the range ofabout 15 to about 350 mg/g of the dosage form, wherein about 80% of thefirst active ingredient dissolves within about the first 60 minutesfollowing entry of the dosage form into a use environment; and whereinthe modified release component comprises a second plurality of beads,each bead comprising a second active ingredient comprising magnesium ora salt thereof in the range of about 15 to about 350 mg/g of the dosageform, wherein about 70% to about 80% of the second active ingredientdissolves within about 4 hours to about 24 hours following entry of thedosage form into the use environment.

The composite dosage form may be combined into a single dosage formhaving a uni-phase or multi-phase profile. The active ingredient, e.g.,magnesium threonate, in the composition may be present in amountsmeasured as mg per dose, ranging from about 2.5 mg to about 100 mg perdose. Preferably, the doses contain 2.5 mg to 80 mg active ingredient.In other embodiments, the dose is 3, 6, 7, 9, 12, 14, 15, 20, 21, 28, 40or 60 mg.

The compositions including an IR and CR component may include an amountof magnesium in the immediate release form of approximately 5% to 90% ofthe composition of the invention. In some embodiments, the immediaterelease portion is about 10% to 60%. In some embodiments, the immediaterelease magnesium content ranges from about 15% to 50%. The controlledrelease form of the magnesium may constitute the remainder of the activeingredient. As a result, a final composition provides an amount ofmagnesium for immediate release following administration and anadditional amount for sustained/modified release. The composition of theinvention may exhibit more than one peak in the plasmaconcentration/time curve in any one dosing interval depending on aparticular active ingredient used, relative amounts of the IR and CRcomponents, and the dissolution properties of the CR component. Thus,compositions may be achieved that have specific release profiles.

The compositions including an IR and CR component may include any solidoral dosage forms known in the art. E.g., solid dosage forms used in thepresent invention include beads. Beads are dose proportional, i.e., thesame proportions of beads of different types can be used for differentdoses without significantly altering the percentage of active ingredientreleased over time. For example, a 40 mg dose will deliver twice themagnesium as a 20 mg dose, with proportional bioavailability. Differentdoses are obtained by using different amounts of beads. Beads alsoenable a variety of dissolution profiles by mixing one or more types ofbeads with different dissolution properties or using multi-layercoatings, as additional layering of active ingredients over a polymerlayer and subsequent coatings to prepare unitary beads, as familiar toone skilled in the art. Beads also enable a wide range of loading. Forexample, magnesium beads may be loaded on beads at up to 500 mg/g dosageform, depending on the form of magnesium, counter ions, and the like.One skilled in the art will recognize that higher loading allows forsmaller capsule size.

Prolonging the time to maximum plasma concentration as compared toimmediate release tablet, is related to the release rate of themagnesium in the use environment. The release rate of the magnesiumdepends on many factors, including the composition of the solid dosageforms and the dissolution properties. By using different compositionscontaining either unitary beads or a combination of a plurality of beadtypes, their individual release rates can be combined to achieve desiredplasma release profiles. Beads with different release characteristicscan be achieved by selection of the release-modifying polymer, as wellas the combination of the release-modifying polymer and the binder toimpart different release characteristics to the resulting beds.Overcoats such as enteric coatings can also be used, if desired.

The beads or bead mixtures may be used, for example, in suspensions,filled into capsules, compressed into tablets, or filled into sachets.One or more types of modified release beads can be mixed together andencapsulated, or used as a sprinkle on the subject's food. According tothe invention, the oral solid dosage form may be any of these forms.Preferably, the dosage form is a capsule.

In one embodiment of the invention, the beads are formulated intocapsules with the use of an encapsulation machine. Various capsule sizesmay be required to accommodate the strength and fill weight of thetarget formulations. Capsule size range from 00 to 5 for fill weightsranging from about 15 mg to about 630 mg.

The particle sizes of the IR and CR bead components in the dosage formdepend on the technology used to prepare them. The particle sizescomponent range from submicron to 500 μm for powder technologies(mixtures, spray drying, dispersions etc), 5 to 1700 μm for coatingtechnologies (Wurster®, top spray, bottom spray, spray drying,extrusion, layering, etc.), to 1-40 mm for tabletting technologies.

In addition to the active ingredients comprising magnesium andthreonate, the oral dosage forms of the present invention can compriseany numbers of physiologically acceptable excipients, depending in parton the controlled release mechanism to be used. “PhysiologicallyAcceptable” includes molecular entities and compositions that do notproduce an adverse, allergic or other untoward reaction whenadministered to an animal, or a human, as appropriate, e.g., those thatare pharmaceutically acceptable. “Physiologically Acceptable Carrier”includes any and all solvents, dispersion media, coatings, antibacterialand antifungal agents, isotonic and absorption delaying agents and thelike. The use of such media and agents for physiologically activesubstances is well known in the art. Except insofar as any conventionalmedia or agent is incompatible with the active ingredient, its use inthe magnesium threonate compositions is contemplated. Supplementaryactive ingredients can also be incorporated into the compositions.“Physiologically Acceptable Salts” include acid addition salts and whichare formed with inorganic acids such as, for example, hydrochloric orphosphoric acids, or such organic acids as acetic, oxalic, tartaric,mandelic, and the like. Salts formed with the free carboxyl groups canalso be derived from inorganic bases such as, for example, sodium,potassium, ammonium, calcium, or ferric hydroxides, and such organicbases as isopropylamine, trimethylamine, histidine, procaine and thelike. General techniques for formulation and administration are found in“Remington: The Science and Practice of Pharmacy, Twentieth Edition,”Lippincott Williams & Wilkins, Philadelphia, Pa. Tablets, capsules,pills, powders, granules, dragees, gels, slurries, ointments, solutionssuppositories, injections, inhalants and aerosols are examples of suchformulations.

By way of example, extended or modified release oral formulation can beprepared using additional methods known in the art. For example, asuitable extended release form of the magnesium threonate compositionsprovided herein may be a matrix tablet or capsule composition. Suitablematrix forming materials include, for example, waxes (e.g., carnauba,bees wax, paraffin wax, ceresine, shellac wax, fatty acids, and fattyalcohols), oils, hardened oils or fats (e.g., hardened rapeseed oil,castor oil, beef tallow, palm oil, and soya bean oil), and polymers(e.g., hydroxypropyl cellulose, polyvinylpyrrolidone, hydroxypropylmethyl cellulose, and polyethylene glycol). Other suitable matrixtabletting materials are microcrystalline cellulose, powdered cellulose,hydroxypropyl cellulose, ethyl cellulose, with other carriers, andfillers. Tablets may also contain granulates, coated powders, orpellets. Tablets may also be multi-layered. Multi-layered tablets areuseful when the active ingredients, e.g., different forms of magnesiumand threonate, have markedly different pharmacokinetic profiles.Optionally, the finished tablet may be coated or uncoated.

The coating composition typically contains an insoluble matrix polymer(approximately 15-85% by weight of the coating composition) and a watersoluble material (e.g., approximately 15-85% by weight of the coatingcomposition). Optionally an enteric polymer (approximately 1 to 99% byweight of the coating composition) may be used or included. Suitablewater soluble materials include polymers such as polyethylene glycol,hydroxypropyl cellulose, hydroxypropyl methyl cellulose,polyvinylpyrrolidone, polyvinyl alcohol, and monomeric materials such assugars (e.g., lactose, sucrose, fructose, mannitol and the like), salts(e.g., sodium chloride, potassium chloride and the like), organic acids(e.g., fumaric acid, succinic acid, lactic acid, and tartaric acid), andmixtures thereof. Suitable enteric polymers include hydroxypropyl methylcellulose, acetate succinate, hydroxypropyl methyl cellulose, phthalate,polyvinyl acetate phthalate, cellulose acetate phthalate, celluloseacetate trimellitate, shellac, zein, and polymethacrylates containingcarboxyl groups.

The coating composition may be plasticised according to the propertiesof the coating blend such as the glass transition temperature of themain component or mixture of components or the solvent used for applyingthe coating compositions. Suitable plasticisers may be added from 0 to50% by weight of the coating composition and include, for example,diethyl phthalate, citrate esters, polyethylene glycol, glycerol,acetylated glycerides, acetylated citrate esters, dibutylsebacate, andcastor oil. If desired, the coating composition may include a filler.The amount of the filler may be 1% to approximately 99% by weight basedon the total weight of the coating composition and may be an insolublematerial such as silicon dioxide, titanium dioxide, talc, kaolin,alumina, starch, powdered cellulose, MCC, or polacrilin potassium.

The coating composition may be applied as a solution or latex in organicsolvents or aqueous solvents or mixtures thereof. If solutions areapplied, the solvent may be present in amounts from approximate by25-99% by weight based on the total weight of dissolved solids. Suitablesolvents are water, lower alcohol, lower chlorinated hydrocarbons,ketones, or mixtures thereof. If latexes are applied, the solvent ispresent in amounts from approximately 25-97% by weight based on thequantity of polymeric material in the latex. The solvent may bepredominantly water.

The compositions of the present invention comprise one or anycombinations of excipients such as, but not limited to, diluents,binders, disintegrants, glidants, lubricants, colorants, flavouringagents, solvents, film forming polymers, plasticizers, opacifiers,antiadhesives, and polishing agents. The compositions of the presentinvention may be formulated using any of the following excipients orcombinations thereof.

TABLE 1 Excipients Excipient name Chemical name Exemplary FunctionAvicel PH102 Microcrystalline Cellulose Filler, binder, wicking,disintegrant Avicel PH101 Microcrystalline Cellulose Filler, binder,disintegrant Eudragit RS-30D Polymethacrylate Poly(ethyl acrylate, Filmformer, tablet binder, tablet nethyl methacrylate, diluent; Ratecontrolling polymer for timethylammonioethyl methacrylate controlledrelease chloride) 1:2:0.1 Methocel K100M Premium CR Hydroxypropylmethylcellulose Rate controlling polymer for controlled release; binder;viscosity-increasing agent Methocel K100M Hydroxypropyl methylcelluloseRate controlling polymer for controlled release; binder;viscosity-increasing agent Magnesium Stearate Magnesium StearateLubricant Talc Talc Dissolution control; anti-adherent, glidant TriethylCitrate Triethyl Citrate Plasticizer Methocel E5 Hydroxypropylmethylcellulose Film-former Opadry ® Hydroxypropyl methylcelluloseOne-step customized coating system which combines polymer, plasticizerand, if desired, pigment in a dry concentrate. Surelease ® AqueousEthylcellulose Dispersion Film-forming polymer; plasticizer andstabilizers. Rate controlling polymer coating.

The magnesium compositions described herein may also include a carriersuch as a solvent, dispersion media, coatings, antibacterial andantifungal agents, isotonic and absorption delaying agents. The use ofsuch media and agents for pharmaceutically active substances is wellknown in the art. Acceptable salts can also be used in the composition,for example, mineral salts such as hydrochlorides, hydrobromides,phosphates, or sulfates, as well as the salts of organic acids such asacetates, proprionates, malonates, or benzoates. The composition mayalso contain liquids, such as water, saline, glycerol, and ethanol, aswell as substances such as wetting agents, emulsifying agents, or pHbuffering agents. Liposomes, such as those described in U.S. Pat. No.5,422,120, entitled “Heterovesicular liposomes,” PCT applications WO95/13796, entitled “Vesicles with Controlled Release of Actives,” or WO91/14445, entitled “Heterovesicular Liposomes,” or European patent EP524,968 B1, may also be used as a carrier.

The oral dosage forms of the present invention can comprise a variety ofexcipients. Surfactants which may be used in the present invention as acompressibility augmenting agent generally include all physiologicallyacceptable, e.g., pharmaceutically-acceptable, surfactants. Suitableanionic surfactants include, for example, those containing carboxylate,sulfonate, and sulfate ions. Those containing carboxylate ions aresometimes referred to as soaps and are generally prepared bysaponification of natural fatty acid glycerides in alkaline solutions.The most common cations associated with these surfactants are sodium,potassium, ammonium and triethanolamine. The chain length of the fattyacids range from 12 to 18. Although a large number of alkyl sulfates areavailable as surfactants, one particularly preferred surfactant issodium lauryl sulfate, which has an HLB value of about 40.

In the formulation arts, sodium lauryl sulfate has been used as anemulsifying agent in amounts of up to about 0.1% by weight of theformulation. Sodium lauryl sulfate is a water-soluble salt, produced asa white or cream powder, crystals, or flakes and is used as a wettingagent and detergent. Also known as dodecyl sodium sulfate, sodium laurylsulfate is actually a mixture of sodium alkyl sulfates consistingchiefly of sodium lauryl sulfate. Sodium lauryl sulfate is also known assulfuric acid monododecyl ester sodium salt. Furthermore, sodium laurylsulfate is readily available from commercial sources such as Sigma orAldrich in both solid form and as a solution. The solubility of sodiumlauryl sulfate is about 1 gm per 10 ml/water. The fatty acids of coconutoil, consisting chiefly of lauric acid, are catalytically hydrogenatedto form the corresponding alcohols. The alcohols are then esterifiedwith sulfuric acid (sulfated) and the resulting mixture of alkylbisulfates (alkyl sulfuric acids) is converted into sodium salts byreacting with alkali under controlled conditions of pH.

Alternative anionic surfactants include docusate salts such as thesodium salt thereof. Other suitable anionic surfactants include, withoutlimitation, alkyl carboxylates, acyl lactylates, alkyl ethercarboxylates, N-acyl sarcosinates, polyvalent alkyl carbonates, N-acylglutamates, fatty acid, polypeptide condensates and sulfuric acidesters.

In other aspects of the invention amphoteric (amphipathic/amphiphilicsurfactants), non-ionic surfactants and/or cationic surfactants areincluded in the coprocessed compositions of the invention. Suitablenon-ionic surfactants such as, for example, polyoxyethylene compounds,lecithin, ethoxylated alcohols, ethoxylated esters, ethoxylated amides,polyoxypropylene compounds, propoxylated alcohols,ethoxylated/propoxylated block polymers, propoxylated esters,alkanolamides, amine oxides, fatty acid esters of polyhydric alcohols,ethylene glycol esters, diethylene glycol esters, propylene glycolesters, glycerol esters, polyglycerol fatty acid esters, SPAN's (e.g.,sorbitan esters), TWEEN's (i.e., sucrose esters), glucose (dextrose)esters and simethicone.

Other suitable surfactants include acacia, benzalkonium chloride,cholesterol, emulsifying wax, glycerol monostearate, lanolin alcohols,lecithin, poloxamer, polyoxyethylene, and castor oil derivatives. Thoseskilled in the art will further appreciate that the name and/or methodof preparation of the surfactant utilized in the present invention isnot determinative of the usefulness of the product.

Highly polar molecules may also be utilized as the compressibilityaugmenting agent. Such highly polar molecules include certain dyes,particular those which may be capable of binding to the cellulosesurface while thereafter creating a relatively hydrophobic environmentdue to the presence of a hydrophobic portion of the molecule (e.g., ahydrophobic tail) which “points away” from the cellulose surface anddiscourages hydrophilic surface-to-surface cellulose interactions, suchas hydrogen-bonding. Preferably, the dye is one which is physiologically(e.g., pharmaceutically) acceptable for inclusion in solid dosage forms.

Examples of suitable dyes include Congo Red (chemical name:3,3′-[[1,1′Biphenyl]-4,4′-diylbis-(azo)]bis[4-amino-1-naphthalenesulfonicacid]disodium salt; FD&C Red No. 40 (also known as “Allura Red”)(chemical name: Disodium salt of6-hydroxy-5[(2-methyl-4-sulfophenyl)azo]-2-naphthalenesulfonic acid);FD&C Yellow No. 5 (common name: tartrazine) (chemical name:5-oxo-1-(p-sulfophenyl)-4-[(p-sulfophenyl)azo]-2-pyrazoline-3-carboxylicacid, trisodium salt); FD&C Yellow No. 6 (common name: Sunset YellowFCF) (chemical name: Disodium salt of1-p-sulphophenylazo-2-naphthol-6-sulfonic acid); Ponceau 4R (chemicalname: Trisodium-2-hydroxy-1-(4-sulfonato-1-naphthylazo)naphthalene-6,8-disulfonate); Brown HT (chemical name: Disodium4,4′-(2,4-dihydroxy-5-hydroxymethyl-3,3-phenylenebisazo)di(napthalene-1-sulfonate)); Brilliant Black BN (Chemical name:Tetrasodium4-acetamido-5-hydroxy-6-[7-sulfonato-4-(4-sulfonatophenylazo)-1-naphthylazo]naphthalene-1,7-disulfonate);Carmoisine (chemical name: Disodium4-hydroxy-3-(4-sulfanato-1-naphythylazo)Naphthalene-1-sulfonate);Amaranth (chemical name: Trisodium2-hydroxy-1-(4-sulfonato-1-naphthylazo) naphthalene-3,6-disulfonate);and mixtures thereof.

Other highly polar molecules which may be utilized as thecompressibility augmenting agent include optional additional activeagents themselves. For example, it is well-known to those skilled in theart that certain classes of pharmaceuticals, such as anti-psychoticdrugs, are highly polar in nature and may be utilized as acompressibility augmenting agent in accordance with this invention.

The usable concentration range for the selected surfactant depends inpart upon not only its molecular weight but also its degree of foaming,particularly when present in agitated slurries which will be spray driedto form the desired particulate. Thus, in those aspects of the inventionwhere surfactants other than sodium lauryl sulfate are coprocessed withthe magnesium threonate, it is to be understood that the surfactant willbe present in an amount which enhances the compressibility of themagnesium threonate and yet does not have a degree of foaming whichwould substantially inhibit spray drying.

In an embodiment utilizing a spray-drying process, an aqueous dispersionof magnesium threonate and a compressibility augmenting agent (forexample, a surfactant or silicon dioxide) is brought together with asufficient volume of hot air to produce evaporation and drying of theliquid droplets. The highly dispersed slurry is pumpable and capable ofbeing atomized. It is sprayed into a current of warm filtered air, whichsupplies the heat for evaporation and conveys a dried product to acollecting device. The air is then exhausted with the removed moisture.The resultant spray-dried powder particles may be approximatelyspherical in shape and may be relatively uniform in size, therebypossessing excellent flowability. The coprocessed particles are notnecessarily uniform or homogeneous. Other drying techniques such asflash drying, ring drying, micron drying, tray drying, vacuum drying,radio-frequency drying, and possibly microwave drying, may also be used.

Alternatively, all or part of the excipient may be subjected to a wetgranulation with an active ingredient. A representative wet granulationincludes loading the novel excipient particles into a suitablegranulator, such as those available from Baker-Perkins, and granulatingthe particles together with the active ingredient, preferably using anaqueous granulating liquid. In some embodiments, a portion of the totalamount of the novel excipient is wet granulated with the activeingredient, and thereafter the additional portion of the novel excipientis added to the granulate. In yet other embodiments, the additionalportion of the novel excipient to be added to the excipient/activeingredient granulate may be substituted with other excipients commonlyused by those skilled in the art, depending of course upon therequirements of the particular formulation.

In other embodiments of the invention, a further material is added tothe magnesium threonate and/or compressibility augmenting agent. Suchadditional materials include silicon dioxides, non-silicon metal oxides,starches, starch derivatives, surfactants, polyalkylene oxides,cellulose A ethers, celluloses esters, mixtures thereof, and the like.Specific further materials which may be included in the aqueous slurry(and consequently in the resultant agglomerated microcrystallinecellulose excipient) are aluminum oxide, stearic acid, kaolin,polydimethylsiloxane, silica gel, titanium dioxide, diatomaceous earth,corn starch, high amylose corn starch, high amylopectin corn starch,sodium starch glycolate, hydroxylated starch, modified potato starch,mixtures thereof, and the like. These additives may be included indesired amounts which will be apparent to those skilled in the art.

In addition to one or more active ingredients, additional additivesknown to those skilled in the art can be added to the novel excipientprior to preparation of the final product. For example, if desired, anygenerally accepted soluble or insoluble inert filler (diluent) materialcan be included in the final product (e.g., a solid dosage form). Suchinert fillers may comprise a monosaccharide, a disaccharide, apolyhydric alcohol, inorganic phosphates, sulfates or carbonates, and/ormixtures thereof. Examples of suitable inert fillers include sucrose,dextrose, lactose, xylitol, fructose, sorbitol, calcium phosphate,calcium sulfate, calcium carbonate, microcrystalline cellulose, mixturesthereof, and the like.

An effective amount of any generally accepted lubricant, includingcalcium or magnesium soaps may optionally be added to the excipient atthe time the magnesium is added, or in any event prior to compressioninto a solid dosage form. The lubricant may comprise, for example,magnesium stearate in any amount of about 0.5-3% by weight of the soliddosage form. In embodiments where a surfactant is included as part orall of the compressibility augmenting agent, an additional inclusionlubricant may not be necessary.

The complete mixture, in an amount sufficient to make a uniform batch oftablets, may then subjected to tableting in a conventional productionscale tableting machine at normal compression pressures for thatmachine, e.g., about 1500-10,000 lbs/sq in. The mixture should not becompressed to such a degree that there is subsequent difficulty in itshydration when exposed to gastric fluid.

The tablets of the present invention may also contain effective amountsof coloring agents, (e.g., titanium dioxide, F.D. & C. and D. & C. dyes;see the Kirk-Othmer Encyclopedia of Chemical Technology, Vol. 5, pp.857-884, hereby incorporated by reference), stabilizers, binders, odorcontrolling agents, and preservatives.

In some embodiments, the magnesium (Mg) is complexed with an anionselected from the group consisting of chloride, laminate, lactate,gluconate, citrate, malate, succinate, sulfate, propionate, hydroxide,oxide, orotate, phosphate, borate, salicylate, carbonate, bromide,stearate, an amino acid, butyrate, aspartate, ascorbate, picolinate,pantothenate, nicotinate, benzoate, phytate, caseinate, palmitate,pyruvate, and threonate. In some embodiments, the oral dosage formscomprise a metal ion selected from the group consisting of calcium,potassium, sodium, chromium, iron, selenium, zinc, manganese,molybdenum, vanadium, and lithium. In some embodiments, one or moreantioxidants are added to the composition, e.g., resveratrol, ellagicacid, quecertin, lipoic acid or vitamin C.

In addition to the excipients listed above, the oral dosage forms of thepresent invention contain one or more chemicals or one or more extractsobtained from the nature. Listed below are examples of nutritionalingredients and health ingredients that can be provided according to thepresent invention.

Examples of nutritional ingredients with which magnesium threonate canbe mixed include 5-HTP (5-hydroxytryptophan), 7-keto-DHEA(dehydroepiandrosterone), acetate, acetyl-L-carnitine, AE-941,α-carotene, α-hydroxy acids, α-aminohydrocinnamic acid, α-ketoglutarate,α-galactosidase, α-linolenic acid, α-lipoic acid, α-tocopherol, SHA-10,androstenediol, androstenedione, arginine, aspartic acid (aspartate),ascorbic acid, β-alanine, β-alanyl-L-histidine, β-carotene,β-cryptoxanthin, β-D-fructofuranosidase, betadine, β-glucan, β-glycans,betaine, β-sitosterol, β-tocopherol, BMS-214778, calcium carbonatematrix, calcium phosphate, caprylic acid, canthaxanthin, CDP-choline,chelated calcium, cholecalciferol, choline, chondroitin sulfate,citicoline, citric acid, creatine, cryptoxanthin, cysteine, D-calciumpantothenate, dehydroepiandrosterone, delta-tocopherol, dexpanthenol,dextran-iron, DGL (deglycyrrhiziated licorice), EA(Dehydroepiandrosterone), dibencozide, dichloroacetate, dimethylglycine,dimethylsulfone, disodium disuccinate astaxanthin, D,L-phenylalanine,DMAE (Dimethylaminoethanol), D-mannose, DMSO (dimethyl sulfoxide),docosahexaenoic acid, docusate sodium, eburnamenine-14-carboxylic acid,EDTA (ethylenediamine tetraacetic acid), EFA (essential fatty acid),ellagic acid, eicosapentaenoic acid, ferrous gluconate, ferrous sulfate,5-hydroxytryptophan, flavonoid, folacin, folate, folic acid, forskolin,fructo-oligosaccharides, GABA (gamma-aminobutyric acid), galanthaminehydrobromide, γ-carotene, γ-linolenic acid, γ-oryzanol,γ-glutamylcysteinylglycine, γ-tocopherol, glucosamine, glucosaminesulfate, glutamine, glutamic acid, glutathione, glycerol,glycerophosphocholine, glycine, histidine, HMB(β-hydroxy-β-methylbutyrate monohydrate), hydroxocobalamin,hydroxycitric acid, hydroxymethylbutyrate, hydroxytryptophan, hyoscinebutylbromide (scopolamine), hydroxylysine, hydroxyproline, hypoxanthineriboside, indole-3-carbinol, inosine, inositol hexanicotinate, inositolhexaphosphate, isoascorbic acid, isoflavones, isoleucine, lactic acid,L-arginine, L-ascorbic acid, L-asparagine, L-carnitine, L-Dopa, leucine,L-phenylalanine, L-tryptophan, luzindole, lycopene, lysine, malic acid,mesoglycan, methionine, methylcobalamin, methylguanidine acetic acid,methylsulfonylmethane, monounsaturated fatty acid, N-3 fatty acids,N-acetyl cysteine, N-acetyl D-glucosamine, N-acetyl-5-methoxytryptamine,N-acetylaspartic acid, NADH, niacin, nicotinamide adenine dinucleotide,nordihydroguaiaretic acid (NDGA), octacosanol, octanoic acid,oleuropein, omega-3 fatty acids, omega-6 fatty acids, omega-9 fattyacid, PABA (para-aminobenzoic acid), pangamic acid, pantethine,pantothenic acid, pantothenol, perillyl alcohol, PGG-glucan,phenylacetate, phosphatidylcholine, phosphatidylserine, phytoestrogen,phytonadione, phytosterols, polyphenols, polysaccharide-K,polyunsaturated fatty acids, polyvinylpyrrolidone-iodine, potassium,potassium aspartate, potassium phosphate, povidone-iodine, pregnenolone,progesterone, provitamin a, pteroylglutamic acid, pyridoxine,pyridoxal-5-phosphate, quercetin, quercetin-3-rhamnoglucoside,quercetin-3-rutinoside, quinine, resveratrol, retinol, riboflavin,riboflavin-5-phosphate, salicin, salicylate, SAM-e(S-adenosylmethionine), sitostanol, sitosterol, sitosterolins, sodiumalginate, sodium ascorbate, sodium chloride, sodium ferric gluconate,sodium iodide, sodium phenylacetate, sodium phosphate, sorbic acid,stigmasterol, sulforaphane, synephrine, tannic acid, theanine,theobromine, thiamin, thioctic acid, tocopherols, tocotrienols,triacylglycerol lipase, tricholine citrate (TRI), troxerutin,tryptophan, tyrosine, acetyl-L-tyrosine, ubidecarenone, ubiquinone,urosolic acid, usnic acid, valine, vitamin A, vitamin B1, vitamin B12,vitamin B2, vitamin B3, vitamin B5, vitamin B6, vitamin B9, vitamin Bx,vitamin C, vitamin D, vitamin D2, vitamin D3, vitamin E, vitamin G,vitamin H, vitamin K, vitamin M, vitamin O, vitamin Q10, xylitol, orzeaxanthin.

Examples of nutritional ingredients which are herbal or natural extractswith which magnesium threonate can be incorporated include aaron's rod(verbascum thapsus), abelmoschus moschatus, abrus precatorius, absinthe,abuta, acacia, acacia senegal, acai, acemannan, acerola, achicoria,achillea millefolium, achiote, ackee, aconite, aconitum napellus, acornscalamus L., actaea racemosa L., actinidia chinensis, actinidiadeliciosa, adam's needle, adelfa, adrue, aegle marmelos, aesculushippocastanum L., african wild potato, agathosma betulina, agaveamericana, agave sisalana, agrimonia eupatoria, agrimonia odorata,agrimonia procera, agrimony, agropyron repens, aguacate, alanine,albahaca morada, albaricoque, albarraz, alchemilla vulgaris, alcusa,alder, alfalfa, algarrobo, algin, alizarin, alkanet tinctoria, alliumcepa, allium sativum, allium ursinum, allspice, almendra amarga,almendra dulce, aloe, aloe barbadensis, aloe ferox, aloe vera, alpinecranberry, alpinia galanga, alpinia officinarum, althaea officinalis,aluminum phosphate, amanita muscaria, amaranth, amargo, ambrette(abelmoschus moschatus), american aloe, american hellebore, americanpawpaw, american pennyroyal, american scullcap, american valerian,american white water lily, american yew, aminobenzoic acid, amla fruit,ammi visnaga, amomum, anacardium occidentale, ananas comosus, ananassativus, anapsos, anchusa, andiroba, andrographis paniculata, anemoneacutiloba, angelica sinensis, angel's trumpet, angostura trifoliata,anis estrellado, annatto, annona muricata, annual mugwort, annualwormwood, antelaea azadirachta, anthemis grandiflorum, anthemis nobilis,anthozoa, antineoplastones, antineoplastons, AFA (aphanizomenonflos-aquae), apis cerana, apis mellifera, apium graveolens, apocynumcannabinum, apple cider vinegar, apricot, arachis hypogaea, arbrefricassee, arbutin, arcilla, arctium lappa, arctium majus,arctostaphylos, arctostaphylos uva-ursi, areca catechu L., arecoline,aristolochia, armeniaca vulgaris, armoracia rusticana, arnica montana,arrowroot, arsenicum album, artemisia absinthium, artemisia annua,artemisia vulgaris, arthrospira plantensis, artichoke, artocarpusheterophyllus, arundinaria japonica, asafoetida, asarabacca, asarum,asclepias tuberosa, ascophyllum nodosum, ashwagandha, asian ginseng,asimina americana, asimina triloba, asophyllum nodosum, aspalathuslinearis, asparagus, asparagus officinalis, aspen, asperula odorata,aspérula olorosa, astaxanthin, astaxantina, asthma weed, astrágalo,astragalus, astragalus membranaceus, atropa belladonna, australian teatree oil, autumn crocus, aveloz, avena extract, avocado, azadirachtaindica, ba ji tian, babassu, baccharis genistelloides, baccharistrimera, baccharis triptera, bacopa, bacopa monnieri, bael fruit, baikalskullcap, ballota nigra, balm of gilead, balsam herb, bamboo, bantutulip, banxia houpo tang, baptisia australis, barbados cherry, barberry,bardana, barosma betulina, bay leaf, bayberry, bear's garlic, bearberry,bedstraw, bee pollen, beeswax, beet, bejunco de cerca, belcho (ephedrasinica), belladona, bellis perennis, bentonite, berberina, berberine,berberis aristata, berberis vulgaris, bergamot oil, β-vulgaris, betelnut, betony, betula spp., bifidobacteria, bilberry, biminne, bing gantang, birch sugar, birthwort, bishop's weed, bismuth, bitter almond,bitter aloe, bitter ash, bitter gourd, bitter melon, bitter orange,bitter wood, bitterroot, bixa orellana, biznaga, black bryony, blackcohosh, black currant, black haw, black horehound, black mulberry, blackmufstard oil, black pepper, black seed, black tea, blackberry, blackcherry, black walnut, bladderwrack, blessed thistle, blighia sapida,bloodroot, blue cohosh, blue flag root, blue rocket (aconite),blueberry, blue-green algae, bluperum, boldo, boneset, borage seed oil,borago officinalis, borforsin, boswelia carterii, boswellia sacra,boswellia serrata, bovine cartilage, boxwood, brahmi, brassicacampestris oil, brassica nigra, brassica oleracea, brazilian vetiver,bromelain, broom corn, brugmansia, bryonia, b-sitosterol, buchu,buckhorn plantain, buckshorn plantain, buckthorn, buckwheat, bugleweed,bulbous buttercup, bupleurum, burdock, butanediol, butcher's broom,butterbur, buxus sempervirens L., cabbage rose, cactus prickly pear,cajeput oil, calaguala, calamus, calcitriol, calendula, californiajimson weed, california poppy, calophyllum inophyllum L., calostrobovino, camellia sinensis, campesterol, camphor, canadian hemp, cancerweed, cannabis sativa, canola oil, cantharis, capsella bursa-pastoris,capsicum, carapa ssp., caraway, caraway oil, carbohydrate supplement,cardamom, cardamomo, cardo bendito, cardo lechero, carica papaya,carnitine, carnosine, carob, carotene, carqueja (baccharisgenistelloides), carrageenan, carrot, carthamus tinctorius, cascarasagrada, cashew, castaña de indias, castor oil, castor seed, caterpillarfungus, catha edulis, catnip, cat's claw, cat's hair, catuaba,caulophyllum thalictroides, cayenne, cebada, cebolla albarrana, cedarleaf oil, celandine, cemphire, centaurea benedicta, centaurea cyanus,centella asiatica, century plant (agave americanan), cephaelisipecacuanha, ceratonia asiatica, ceratonia siliqua, cervus elaphus,cervus nippon, cetyl myristoleate, ceylon citronella, chamaemelumnobile, chamomile, chaparral, chasteberry, chaste tree, chelidoniummajus, chenopodium quina, chenopodium vulvaria, chewing tobacco, chia,chickweed, chicory, chili pepper, china rose, chinese angelica, chineseboxthorn, chinese foxglove, chinese gelatin, chinese ginger, chineseginseng, chinese matrimony vine, chinese star anise, chinese wormwood,chintul, chirayata, chitosan, chlorella, Cholestin®, chrysanthemum,chrysanthemum vulgare, chrysin, chrysopogon spp., cichorium intybus,cicuta virosa, cider vinegar, cimicifuga racemosa, cinnamomumaromaticum, cinnamon, cissampelos pareira, citrillus colocynthis,citronella grass, citrulline, citrus aurantifolia, citrus aurantium,citrus bergamia, citrus naringinine, citrus paradisi, citrus reticulata,claviceps purpurea, clavo de olor, cloud mushroom, clove, club moss,cnidium monnieri, cobalamin, coca, coccinia indica, cochleariaarmoracia, cockleburr, coconut oil, codonopsis, coenzyme Q10, coenzymeR, cohosh azul, cohosh negro, cola nut, colchicum, coleus forskohlii,coltsfoot, colubrina arborescens, comfrey, commifora mukul, commiphoramolmol, commiphora myrrha, condurango, cone flower, conium maculatum,consuelda, copaiba balsam, copaifera officinalis, coptis formula, coralcalcium, cordyceps sinensis, coriolus mushroom, coriolus versicolor,corn poppy, corn silk, corn sugar gum, cornflower, cornus spp.,corydalis, corylus avellana, corynanthe yohimbi, costmary, cottonseedoil, cottonwood, couch grass, cow parsnip, cowbane, cowhage, cowslip(primula veris), crab's eye, cramp bark, cranberry, cranesbill,crataegus, cumin, creosote bush, cucurbita pepo, cupressus sempervirens,curcuma domestica, curcuma longa, curcumin, curly dock, cuspariafebrifuga, cusparia trifoliata, cuspidatum, custard apple, cyamopsistetragonolobus, cyanocobalamin, cymbopogon spp., cynara scolymus,cyperus articulatus, cypress, cypripedium acaule, cypripedium calceolus,cystadane, cytisus scoparius, daio-kanzo-to, daisy, damiana, dandelion,dangshen (or danshen), date palm, datura meteloides, datura sauveolens,datura stramonium, datura wrightii, daucus carota, deadly nightshade,deanol, deer velvet, desert parsley, devil's claw, devil's club, dihuang, diente de león, diet, macrobiotic, dietary fiber, dietarysaccharides, digitalis, dill, dioscorea communis, dioscorea villosa L.,diviner's sage, dogwood, dolichos pruriens, dolomite, dong quai,D-pantothenic acid, D-phenylalanine, dromaius novaehollandiae, drosera,dumontiaceae, dutchman's pipe, eastern hemlock, echinacea, echinaceaangustifolia, echinacea purpurea, echium, elderberry, elecampane,electro colloidal silver, elemental iron, elettaria cardamomum, eleusineindica, elletaria cardamomum, elymus repens, emu oil, enebrina, englishchamomile, english ivy, english walnut, english yew, ephedra, EGCG(Epigallocatechin gallate), epilobium angustifolium, epilobiumparviflorum, epimedium grandiflorum, equinácea, equisetum arvense L.,ergocalciferol, eriodictyon californicum, erythroxylum vacciniifolium,eschscholzia californica, escoba negra, espirulina, Essiac®, estevia,eucalyptus oil, euforbio, eufrasia, eugenia aromatica, eupatoriumperfoliatum, euphorbia, euphorbiaceae, euphrasia officinalis, europeancranberry, euterpe oleracea, evening primrose oil, evodia rutecarpa,eyebright, fagopyrum esculentum, fennel (foeniculum vulgare mill.),fenugreek, fermented milk, ferula assafoetida, feverfew, fucus carica,fucus inspida, fig, filipendula ulmaria, fireweed, flaxseed and flaxseedoil, fleet phospho-soda, fleet enema, Flor-Essence®, fly agaric, fo-ti,foxglove, fragaria, fragaria vesca, frambuesa, frangula purshiana,frankincense, fraxinus, french rose, friar's cap, fructus barbarum,fucus vesiculosus, fuzheng jiedu tang, gallic acid, galanga, galanthus,galipea officinalis, galium odoratum, gallium aparine, gambierdiscustoxicus, ganoderma lucidum, garcinia cambogia, garcinia mangostana,garcinia, ácido hydroxicítrico, garlic, garra del diablo (harpagophytumprocumbens), gelatin, gelidiella acerosa, gelsemium, genistein, gentian,gentian violet, geranium maculatum, german chamomile, germander,germanio, germanium, germanium sesquioxide, germinated barleyfoodstuffs, giant knotweed, gimnema, gentian, ginger, ginkgo, ginseng,glechoma hederacea, globe artichoke, glycine soja, glycyrrhiza glabra,gobi, goji, goldenrod, goldenseal, goniopora spp., goosegrass, gossypol,gotu kola, gotu kola y fracción triterpénica total de lacentellaasiática (TTFCA), gou qi (chinese wolfberry), gramilla, granada, grapeseed extract, grapefruit, grass pea, graviola, greater celandine,greater galangal, green hellebore, green tea, griffonia, grifolafrondosa, grindelia, grindelia camporum, ground ivy, guar gum, guarana,guayule, guelder rose, guggals, guggul, gum acacia, gum arabic, gumweed,guru nut, gymnema sylvestre, gynostemma pentaphyllum, hamamelis, hangekoboku-to, haritaki, harpagophytum procumbens, hashish, hawthorn,hazelnut, hedeoma pulegioides L., hedera helix, helianthus annuus,hellebore, hemlock, hemp seed oil, hepatica, heracleum maximum,hesperidin, hibiscus, hiedra terrestre, hierba carmin, hierba de cabraen celo (epimedium grandiflorum), hierba de limon (lemon grass), hierbade san juan (hypericum perforatum L.), hierba de trigo (triticumaestivum), high bush cranberry, hippophae rhamnoides, holy basil,hochu-ekki-to, honey, honeysuckle, hongo maitake, hoodia gordonii,hordeum vulgare, horehound, horny goat weed, horse chestnut, horsechestnut seed extract, horse heal, horseradish, horsetail, hou po(magnolia bark), hoxsey formula, huang qi, huang-teng ken, humuluslupulus L., huperzia serrata, huperzine A, hyaluronic acid, hydrangeaarborescens, hydrastis canadensis, hydrazine sulfate, hydrocotyleasiatica, hydrilla, hypericum perforatum, hypoxis hemerocallidea,hypoxis rooperi, hyssopus officinalis, ignacia (or ignatia), illiciumverum, impatiens biflora, impatiens pallida, indian bael, indianbarberry, indian fig, indian licorice, indian mulberry, indian poke,indian snakeroot, indian tobacco, inula campana, inula helenium, ipecac,ipomoea orizabensis, ipriflavone, iris versicolor, isatis indigotica,iscador, isphagula, ivy, jackfruit, jamaican quassia, japanese yew,japanese sophora, jasmine, jengibre, jequirity, jervine alkaloids,jewelweed, jianpi wenshen recipe, jiaogulan, jimson weed, jointedflatsedge, jojoba, joshua tree, juglans regia, juniper, kan Jang®,karaya gum, karkada, katuka, kale, kava (piper methysticum), kefir,kelp, khat (catha edulis), khella (ammi visnaga, also known as khellin),kinetin, kiwi, kiwifruit, klamath weed, kola nut, korean red ginseng,krebiozen, krestin, krill oil, kudzu, labrador tea, lactalbumin,lactobacillus acidophilus, lactobacillus casei, lactobacillus GG,lactobacillus plantarum, lactobacillus reuteri, lactobacillussporogenes, lactobacilo acidófilo, lactoferrin, ladies mantle, lady'sslipper, laetrile, lagerstroemia speciosa L., larch arabinogalactan,larix, larrea divaricata, larrea tridentata, lathyrus, laurus nobilis,laurus persea, lavender, lecithin, ledum groenlandicum, ledumlatifolium, ledum palustre, legume, lei gong teng, lemon balm,lemongrass, lentinan, lentinula edodes, lentinus edodes, lentisco,leonurus cardiaca, lepidium meyenii, lepidium peruvianum chacón, lessercelandine, lesser galangal, lessertia frutescens, levisticum officinale,levoglutamide, lichen, licorice, lignans, ligustrum, lime, lime flower,linden, lingonberry, linseed oil, linum usitatissimum, lipase, lirioazul, lirio de agua blanco (nymphaea odorata), liverwort, L-norvaline,lobelia inflata, locust bean, lomatium, lomatium dissectum, long pepper,lonicera spp., lophosphora spp., lophosphora williamsii, lorenzo's oil,lotus, lousewort, lovage, lucky nut, lúpulo, lutein, luteina,lycopersicon esculentum, lycopodium clavatum, lycopodium serrata,lycopus americanus, lycopus europaeus, lycopus lucidus, lycopusvirginicus, lysichiton americanu, ma huang, maca (lepidium peruvianumchacón), macrobiotic diet, madagascar jewel, madder (rubia tinctorum),maeng lak kha, magic mint, magnolia, magnolia and pinelliae formula,mahonia, maidenhair tree, maitake mushroom, malpidnia glabra, malpighiaglabra, malpighia punicifolia, malus sylvestris, maltas malvavisco,mangaresa, mandarin, mangosteen, manto de nuestra señora (alchemillavulgaris), manzanilla, MAP30, maranta arundinacea, maria pastora,marigold, marijuana, marrubio blanco, marrubium vulgare, marsh tea,marshmallow, marshmallow root, mastic (psitacia lentiscus), matricariarecutita, mauby bark, MCP (modified citrus pectin), meadowsweet,medicago sativa L., melaleuca alternifolia, melaleuca leucadendron,melaleuca quinquenervia, melatonin, melissa officinalis, menaquinones,mentha pulegium L., mentha x piperita L., menthol, mexican scammonyroot, mezereon, microcrystalline cellulose, microcrystallinehydroxyapatite, milenrama, milk bush, milk thistle, mistletoe, modifiedcitrus pectin, momordica charantia L. curcurbitaceae, momordicagrosvenori, monacolin K, monascus purpureus, monkshood, morindacitrifolia, morinda officinalis, moringa, morus nigra, motherwort,mountain balm, moutan, MSM (Methylsulfonylmethane), mucuna pruriens,mugwort, muira puama, mulberry, mullein, musk seed, mustard, myrcia,myrica cerifera, myrrh, narrowleaf plantain, nasturtium officinale,neem, nelumbo nucifera, neovastat, nepeta cataria, nerium oleander,nettle, nexrutine, nicotiana glauca, nicotiana tabacum, nigella sativa,noni (morinda citrifolia), nopal, northern prickly ash, norvaline, nuezde betel (areca catechu L.), nutmeg, nux vomica, nymphaea odorata, oakbark, oak moss, oat beta-glucan, oat bran/straw, oat, ocimum basilicum,ocimum sanctum L., oenothera biennis L., okra, old man's beard, oleaeuropaea, oleander, olibanum, olive leaf, olive oil, olmo resbaladizo,oplopanax horridus, opuntia streptacantha, orbignya phalerata, oregano,oregon grape, origanum vulgare, ornithine, ovoester, oxerutin,oxykrinin, ox bile extract, pacific yew, pagoda tree, palm oil, palmaenana americana (serenoa repens), pamabrom, panax ginseng, papaverrhoeas, parietaria officinalis, parsley, parsnip, parthenium argentatum,parthenolide, pasiflora, passion flower, pastinaca, pastinaca sativa,pau d'arco, paullinia cupana, pausinystalia yohimbe, PC-SPES, peanutoil, pectin, pedicularis, pedra hume caá (myrcia salicifolia),pellitory-of-the-wall, pencil tree, pennyroyal (mentha pulegium), peony,peppermint, peppermint oil, perilla frutescens, periwinkle, perseaamericana, petadolex, petasita, petasites hybridus, petty spurge, peumusboldus, peyote, phaseolamin (white kidney bean), phaseolus vulgarisvarieties, phoenix dactylifera, phoradendron leucarpum, phyllanthus,physalis somnifera, phyto-1, phytolacca americana, picraena excelsa,picrasma excelsa, picrorhiza kurroa, pill-bearing spurge, pimentadioica, pimpinella anisum, pine bark extract, pine pollen, pinusmaritima, pinus palustris, piper methysticum, piper nigrum, pistacialentiscus, plant stanol ester, plantago coronopus, plantago isphagula,plantago lanceolata, plantago ovata, pleurisy, podophyllum hexandrum,podophyllum peltatum, poinsettia, poison ivy, poke root, pokeweed, poleoamericano, policosanol, polygonum cuspidatum, polygonum multiflorum,polypodium leucotomos extract and anapsos, pomegranate, populus, poppy,precatory bean, prickly ash, prickly pear cactus, primula officinalis,primula veris, probeta, promensil, propagermanium, propolis, prunellavulgaris, prunus africanum, prunus amygdalus, prunus amygdulus dulcis,prunus armeniaca, prunus armeniaca L., psyllium, ptychopetalumolacoides, pueraria lobata, pueraria montana var., puerarin, puertorican cherry, pulegone, pulsatilla, pumpkin, pumpkin seed oil, punicagranatum, purple viper bugloss, pycnogenol, pygeum bark, pyrus communis,pyruvate, qing hao, qinghao, qinghaosu, quack grass, quaker bonnet,quaker buttons, quaking aspen, quassia, queen anne's lace, queen offruits (mangosteen fruts), queen of the meadow, queen's crape myrtle,quercus alba, quercus cortex, quercus marina, quick-in-the-hand(jewelweed), quimsa-kuchu, quinoa, quinsu-cucho, quitch grass, rabdosiarubescens, radium weed, radix angelica sinensis, ranunculus bulbosus,ranunculus ficaria, rapeseed oil, raspberry, rauvolfia serpentine, redalgae, red clover, red palm oil, red sorrell, red stinkwood, red yeastrice, regaliz, rehmannia, rehmannia glutinosa, reina de los prados(spiraea ulmaria), reishi mushroom, rennet, rhamnus purshiana, rheumofficinale, rheum palmatum, rhodiola, rhodiola rosea, rhododendrontomentosum, rhubarb, rhus tox, ribes nigrum, rice bran oil, ricola,roble blanco, roman chamomile, romero, rooibos, rosa canina, rosary pea,rose haw, rose hip, rose laurel, roselle, rosemary, rosmarinusofficinalis L., royal jelly, rhubarb, rubus fructicosus, rubus idaeus,rubus villosus, ruibarbo, rumalon, rumex crispus, ruscus aculeatus, rutagraveolens, rutin, rye grass, sabal serrulata, sabila, saccaromycescerevisiae, saccharomyces boulardii, saccharomyces thermophilus,safflower, sage, saiboku-to, saiko-keishi-to, Salba®, salix alba, salixspp., salvia divinorum, salvia hispanica, salvia lavandulaefolia, salvialavandulifolia, salvia miltiorrhiza, salvia officinalis, samambaia,sambucas nigra, sandalwood, sanguinaria canadensis, sanguinarine,santalum album, sarsaparilla, sassafras, sauco berry (sambucus nigra),saw palmetto, schisandra chinensis, schizandra berry, schizandrae,schizopeta, scopolamine, scotch broom, scullcap, scutellariabaicalensis, scutellaria barbata, scutellaria lateriflora, seabuckthorn, seaweed, bladderwrack, secale cereale, secretin, seer sage,sehydrin, sea cucumber, selagine, senna, serine, serenoa repens, sesameoil, seso vegetal, shakuyaku-kanzo-to, shallot, shark cartilage, shengdihuang, shepherd's purse, shepherd's purse, shiitake mushroom,shikonin, sho seiryu to, sho-saiko-to, shuang huang lian, siameseginger, silka deer, silver birch, silver protein, silymarin, simmondsiachinensis, sisal, skunk cabbage, slippery elm, smilax spp., smokelesstobacco, snakeroot, snowball bush, soja, solidago virgaurea, sophora,sorghum vulgare, sorrel, sour cherry, sour orange juice, soy, soy beanextract, soy bran, soy protein, soy sprouts, soybean oil, sparteine,spinach, spirogermanium, spirulina, spurge olive, squill, st. ignatiusbean, st. john's bread, st. john's wort, stachys betonica, stachysofficinalis, star anise, stellaria media, sterculia urens, stevia,stickleburr, stinging nettle, stinking goosefoot, strychnos ignatii,strychnos nux-vomica, styphnolobium japonicum, substance x, sulfato decondroitina, suma (pfaffia paniculata), sunflower seed oil, sutherlandiafrutescens, swamp hellebore, sweet almond, sweet annie, sweet basil,sweet cherry, sweet orange, sweet root, sweet woodruff, sweet wormwood,sweetflag, symphytum, symphytum officinale, symplocarpus foetidus,tadenan, tamanu, tamarind, tamarindus indica L., tamus communis,tanacetum parthenium, tanacetum vulgare, tangerine, tansy, taraxacumofficinale, taurine, tea tree oil, tejo, terminalia, teucriumchamaedrys, theobroma cacao, thevetia peruviana, thuja occidentalis,thunder god vine, thyme (thymus vulgaris), tibetan goji berry, tilofora,toki-shakuyaku-san, toxicodendron radicans (eastern poison ivy),tragacanth, tree tobacco, trembling aspen, tribulus terrestris,trichilia catigua, trierucate oil, trifolium pratense, trigonellafoenum-graecum, trigonella foenum-graecum L. leguminosae,trimethylethanolamine, tripterygium wilfordii, triticum aestivum, tsugacanadensis, TTFCA (total triterpenic fraction of centella asiatica),tuftsin, tulsi holy basil, turkey tail mushroom, turmeric, turneraaphrodisiaca, turnera diffusa, turpentine oil, tussilago farfara,tylophora, tylophora indica, Ukrain™, ulmus rubra/ulmus fulva, umbrellaarum, uncaria guianensis, uncaria tomentosa, urginea maritima, urticadioica, usnea barbata, uva ursi, vaccinium angustifolium, vacciniummacrocarpon, vaccinium myrtillus anthocyanoside, vaccinium vitis-idaea,valerian, velvet deer antler, velvet flower, velvetleaf, veratrumviride, verbascum thapsus, verbena, vervain, vetchling, vetiver(chrysopogon zizanioides), viburnum opulus, viburnum prunifolium,vinagre de sidra de manzana, vinca minor, vinpocetine, viper's bugloss,virginia's herbal E-Tonic™, viscum album L., vitex agnus-castus, vitisvinifera, vulvaria, wasabia japonica, water hemlock, watercress,wheatgrass, wheat bran/grass, wheat germ, wheat sprouts, whey protein,white horehound, white mallow, white oak, white pepper, whitesandalwood, white tea, white water lily, wild arrach, wild carrot, wildcherry, wild ginger, wild indigo, wild marjoram, wild rosemary, wildyam, willow bark, witch hazel, withania somnifera, wintergreen, woodbetony, wolfberry, wormwood, Xango®, xanthan gum, xanthomonascampestris, xhoba, xi yang shen, xi zhang hu huang lian, xian cao, xianling pi, xianxao, xiao qing long tang, xiao-chai-hu-tang, xu ku cao, xuezhi kang, yadake, yagona, yam, yamabushitake mushroom, yang-mei,yangona, yaqona, yarrow, yashti-madhu, yashti-madhuka, yavatikta, yege,yellow astringent, yellow bark, yellow beeswax, yellow beet, yellowbroom, yellow dock, yellow ginseng, yellow horse, yellow indian paint,yellow indigo, yellow jasmine, yellow oleander, yellow poppy, yellowpuccoon, yellow root, yellow sandalwood, yellow saunders, yellowstarwort, yemen myrrh, yerba dulce, yerba mate, yerba santa, yew, yizhu, yin yang huo, yinhsing, yodo, yogaraj guggul gum resin, yohimbebark extract (pausinystalia yohimbe), yongona, yuan hu suo, yucca, yuccaaloifolia, yucca angustifolia, yucca arborescens, yucca breifolia, yuccafilamentosa, yucca glauca, yucca schidigera, yucca whipplei, yun zhi,zanthoxylum americanum, zapatilla de dama, zea mays, Zemaphyte®,zingiber officinale roscoe, or ZMA™. The composition may be used asnutritional supplement, dietary supplement, food supplement, or as afood additive. The composition may be manufactured as a tablet, capsule,liquid, lyophilized powder, powder, crystalline, aerosol, liquidimpregnated onto a dermal patch, ointment, or suppository.

In a related embodiment, the magnesium-counter ion composition may alsocontain other nutritional ingredients including, without limitation,calcium-containing materials such as calcium carbonate, stannol esters,hydroxycitric acid, vitamins, minerals, herbals, spices and mixturesthereof. Examples of vitamins that are available as additionalingredients include, but are not limited to, vitamin A (retinol),vitamin D (cholecalciferol), vitamin E group (alpha-tocopherol and othertocopherols), vitamin K group (phylloquinones and menaquinones),thiamine (vitamin B₁), riboflavin (vitamin B₂), niacin, vitamin B₆group, folic acid, vitamin B₁₂ (cobalamins), biotin, vitamin C (ascorbicacid), and mixtures thereof. The amount of vitamin or vitamins presentin the final product is dependent on the particular vitamin. Examples ofminerals that are available as additional ingredients include, but arenot limited to, calcium, phosphorus, iron, zinc, iodine, selenium,potassium, copper, manganese, molybdenum and mixtures thereof. As is thecase with vitamins, the amount of mineral or minerals present in thefinal product is dependent on the particular mineral. It will be clearto one of skill in the art that the present list of additionalneutriceutical components are provided by way of example only, and arenot intended to be limiting.

In addition to oral dosage forms, the compositions of the presentinvention can be administered to a subject by any available andeffective delivery systems. Such delivery systems include, but are notlimited to, parenteral, transdermal, intranasal, sublingual,transmucosal, intra-arterial, or intradermal modes of administration indosage unit formulations containing conventional nontoxicphysiologically acceptable carriers, adjuvants, and vehicles as desired,such as a depot or a controlled release formulation. Depending on theroute of administration, the magnesium composition of the presentinvention may be formulated as a suppository, lotion, patch, or device(e.g., a subdermally implantable delivery device or an inhalation pump).The compositions may be optimized for particular types of delivery.

In some embodiments of the present invention, magnesium and threonateare delivered in an aerosol spray preparation from a pressurized pack, anebulizer or from a dry powder inhaler. Suitable propellants that can beused in a nebulizer include, for example, dichlorodifluoro-methane,trichlorofluoromethane, dichlorotetrafluoroethane and carbon dioxide.The dosage can be determined by providing a valve to deliver a regulatedamount of the compound in the case of a pressurized aerosol.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable excipients as set out above. Preferably thecompositions of the present invention are administered by the oral,intranasal or respiratory route for local or systemic effect.Compositions in acceptable solvents may be nebulized by use of inertgases. Nebulized solutions may be breathed directly from the nebulizingdevice or the nebulizing device may be attached to a face mask, tent orintermittent positive pressure breathing machine. Solution, suspensionor powder compositions may be administered, preferably orally ornasally, from devices that deliver the formulation in an appropriatemanner.

In some embodiments, for example, the composition may be deliveredintranasally to the cribriform plate rather than by inhalation to enabletransfer of the active agents through the olfactory passages into theCNS and reducing the systemic administration. Devices commonly used forthis route of administration are included in U.S. Pat. No. 6,715,485,entitled “Nasal delivery device.” Compositions delivered via this routemay enable increased CNS dosing or reduced total body burden reducingsystemic toxicity risks associated with certain compositions.

The composition may optionally be formulated for delivery in a vesselthat provides for continuous long-term delivery, e.g., for delivery upto 30 days, 60 days, 90 days, 180 days, or one year. For example thevessel can be provided in a biocompatible material such as titanium.Long-term delivery formulations are particularly useful in subjects withchronic conditions, for assuring improved patient compliance, and forenhancing the stability of the compositions.

According to another embodiment, the composition of the invention is aliquid or semi liquid comprising at least 20 mg/L magnesium, or at least40 mg/L magnesium. In some embodiments, the composition of the inventionis a liquid or semi liquid comprising at least 5 mg/L magnesium, atleast 10 mg/L magnesium, at least 20 mg/L magnesium, at least 30 mg/Lmagnesium, at least 40 mg/L magnesium, at least 50 mg/L magnesium, atleast 60 mg/L magnesium, at least 70 mg/L magnesium, at least 80 mg/Lmagnesium, at least 90 mg/L magnesium, or at least 100 mg/L magnesium.

Alternatively, the compositions of the present invention may beadministered transdermally. Preparation for delivery in a transdermalpatch can be performed using methods also known in the art, includingthose described generally in, e.g., U.S. Pat. Nos. 5,186,938 and6,183,770, 4,861,800, 6,743,211, 6,945,952, 4,284,444, and WO 89/09051,incorporated herein by reference in their entireties. A patch is aparticularly useful embodiment with active agents having absorptionproblems. Patches can be made to control the release of skin-permeableactive ingredients over a 12 hour, 24 hour, 3 day, and 7 day period. Inone example, a 2-fold daily excess of magnesium threonate is placed in anon-volatile fluid. A preferred release can be from 12 to 72 hours.

In some embodiments, for example, the composition may be delivered viaintranasal, buccal, or sublingual routes to the brain rather than byinhalation to enable transfer of the active agents through the olfactorypassages into the CNS and reducing the systemic administration. Devicescommonly used for this route of administration are included in U.S. Pat.No. 6,715,485, entitled “Nasal delivery device.” Compositions deliveredvia this route may enable increased CNS dosing or reduced total bodyburden reducing systemic toxicity risks, e.g., diarrhea.

Preparation of a compositions for delivery in a subdermally implantabledevice can be performed using methods known in the art, such as thosedescribed in, e.g., U.S. Pat. Nos. 3,992,518; 5,660,848; and 5,756,115.Additional methods for making modified release formulations aredescribed in, e.g., U.S. Pat. Nos. 5,422,123, 5,601,845, 5,912,013, and6,194,000, all of which are hereby incorporated by reference.

II. Uses

The present invention provides methods of using the compositionsdisclosed herein. In some embodiments, such uses comprise administeringthe oral dosage forms of the present invention to provide a variety ofhealth benefits. Such a composition may comprise at least onemagnesium-counter ion compound. A magnesium-counter ion compositiondescribed herein may be useful for any of a variety of applications andpurposes described herein, such as maintaining, enhancing, and/orimproving health, nutrition, and/or another condition of a subject,and/or cognitive, learning, and/or memory function, for example.Magnesium deficit may lead to or may be associated with manypathological symptoms, such as loss of appetite, nausea, vomiting,fatigue, seizures, abnormal heart rhythms, diabetes, and/orcardiovascular disease, for example. According to several studies,magnesium deficit may lead to or may be associated with attentiondeficit hyperactivity disorder (ADHD) in children and symptomsassociated therewith (Kozielec et al., Magnes. Res. 10(2), 143-148(1997) and Mousain-Bosc et al., Magnes. Res. 19(1), 46-52 (2006)). Amagnesium-counter ion composition described herein may be useful foradministration to a subject presenting magnesium deficiency, mildcognitive impairment, Alzheimer's disease, attention deficithyperactivity disorder, ALS, Parkinson's disease, diabetes, migraine,anxiety disorder, mood disorder, and/or hypertension, merely by way ofexample.

Magnesium is an essential mineral in the human body and plays a role innumerous physiological functions. Yet, it is generally recognized thatat least half of the people in the industrialized world do not getsufficient magnesium from their diets. Several diseases, such asdiabetes and Alzheimer's disease (AD), are associated with magnesiumdeficit. Therefore, there is a need for magnesium supplementation. Therecommended daily allowance (RDA) for magnesium is about 400 mg foradults. By assuming that people get 40-50% of the required magnesiumfrom diet, the recommended amount of magnesium supplement has generallybeen about 200-250 mg per day for adults. There are numerous magnesiumcompounds that have been used as magnesium supplements. These compoundsinclude magnesium oxide, magnesium citrate, magnesium sulfate, magnesiumchloride, magnesium gluconate, magnesium lactate, magnesium pidolate andmagnesium diglycinate, for example. At least for nutritional purpose,the recommended amount of magnesium supplementation for most commercialmagnesium supplements is about the same (i.e., about 250 mg magnesiumper day), regardless of the bioavailability of the magnesium compoundand the individual's kidney function to retain the amount of theabsorbed magnesium. Some magnesium supplement suppliers have recommendedhigher daily magnesium intake for their products, again, withoutconsidering an individual's kidney function for magnesium retention.Similar to magnesium deficit, an excessive amount of magnesium in thebody (hypermagnesemia) may also lead to health problems, such asneuromuscular depression, hypotension, cardiac arrythmias andrespiratory paralysis. Thus, it is important to have one's bloodmagnesium level stay within the normal range. Disclosed herein is anovel method for controlling the magnesium level to a particular regionof the normal range. In some aspects of the invention, this method alsooffers particular health advantages, such as increased memorycapabilities, increased lifespan, decreased depression, and decreasedsymptoms of neurological disorders, including AD.

In addition to nutritional use, magnesium supplements have been used fortreating type 2 diabetes. In one study, diabetic patients were treatedwith nearly 1 g of magnesium daily using magnesium oxide for 1 month (deLordes Lima, et al., Diabetes Care. 21: 682-6 (1998)). The treatmentincreased the serum magnesium level of the patients by about 10% butwith only minor improvement in metabolic control. In another study,diabetic patients were treated with 720 mg/day of magnesium for threemonths. Similarly, the blood magnesium levels of the patients wereraised by about 10% on average (Eibl, et al., Diabetes Care. 21: 2031-2(1995)). However, the metabolic control of the patients, as assessed bytheir HbA1c levels, had no improvement.

Magnesium ion has been reported to be generally useful for treatment ofdementia (e.g., U.S. Pat. No. 4,985,256, entitled “Methods fordiagnosing, monitoring and controlling the onset and progression ofcertain dementias and impeding memory loss or improving impairment ofmemory”). Landfield and Morgan showed that young (9-month old) and aged(25-month old) rats fed food containing 2% magnesium oxide for 8 dayshad shown some sign of improvement of cognitive function (Landfield andMorgan, Brain Research, 322:167-171 (1984)). However, the gain incognitive function was transient and at the cost of diarrhea and weightloss to the animals. In fact, the side-effect was so severe theresearchers had to use an alternating feeding schedule by having theanimals on the high Mg diet for 4 days, followed by a regular diet fortwo days and then back to the high Mg diet for another 4 days.

Magnesium compounds may also be used to affect bone density. Bonedensity disorders, including but not limited to osteoporosis, may betreated by supplementation with magnesium compounds of the presentinvention. Subjects may be treated to ameliorate the effects of low bonedensity or as prophylaxis against lost bone density. Bone density may bemeasured by any means known in the art, including, but not limited to,dual energy X-ray absorptiometry (DEXA), ultrasound, quantitativecomputed tomography, single energy absorptiometry, magnetic resonanceimaging, measuring metacarpal width, and hand X-ray analysis.

As mentioned above, a magnesium-counter ion composition and/or a methoddescribed herein are useful for various purposes, such as maintaining,enhancing, and/or improving health, nutrition, and/or another conditionof a subject, and/or cognitive, learning, and/or memory function, forexample. Examples of such a condition of a subject include magnesiumdeficiency, mild cognitive impairment, Alzheimer's disease, Huntingdon'sdisease, autism, schizophrenia, cognitive decline as secondary effect ofdisease or medical treatment (HIV disease, cancer, chemotherapy),depression, dementia, attention deficit hyperactivity disorder,Amyotrophic lateral sclerosis (ALS), Parkinson's disease, diabetes,cardiovascular disease (e.g., hypertension), glaucoma, migraine,anxiety, mood, and hypertension, merely by way of example. Magnesiumsupplementation may also be useful in maintaining, enhancing, and/orimproving conditions which may result in loss of body magnesium,including, but not limited to, alcoholism, anorexia, bulemia, metabolicsyndromes, and poor nutrition. Any such condition may be deemed ordefined as a physiological, psychiatric, psychological, or medicalcondition or disorder, for example. Generally, the term “subject” mayrefer to any animal. Examples of such animals include, but are notlimited to, cold-blooded animals, warm-blooded animals, mammals,domesticated mammals, primates, humans, and individuals or a patient towhom a composition is to be administered for experimental, diagnostic,nutritional, and/or therapeutic purposes. A subject or patient may be asubject or patient of normal, good, or excellent health, mood,cognitive, and/or nutritional status, or of compromised health, mood,cognitive, and/or nutritional status, including of abnormal, poor,damaged, unhealthy, impaired, diseased, and/or nutritionally deficientstatus. The subject may be of any age, including advanced age.

Generally, the term “cognition” may refer to a process of obtaining,organizing, understanding, processing, and/or using information orknowledge. Generally, enhancing cognitive function refers to enhancingany aspect of such a process, such as learning, the performance ofmental operations, the storage, retrieval, and/or use of informationand/or thoughts, memory, and/or preventing a decline of a subject'scognitive state, for example. Various standardized tests may be used toevaluate cognition, cognitive function, and/or cognitive state and maybe used to identify a subject who might be conducive to, benefit from,and/or need, maintenance and/or enhancement of same and/or to monitor aneffect of treatment relating to same. Examples of suitable tests includethe Mini-Mental Status Exam (Folstein, 1975), components of the PROSPERneuropsychological test battery (Houx, 2002), and/or the like. Familyhistory, age, and/or other factors may also be used to identify asubject who might be conducive to, benefit from, and/or need,maintenance and/or enhancement of cognition, cognitive function, and/orcognitive state.

Generally, the term “concurrent administration” in reference to two ormore subjects of administration for administration to a subject body,such as components, agents, substances, materials, compositions, and/orthe like, refers to administration performed using dose(s) and timeinterval(s) such that the subjects of administration are presenttogether within the subject body, or at a site of action in the subjectbody, over a time interval in less than de minimus quantities. The timeinterval may be any suitable time interval, such as an appropriateinterval of minutes, hours, days, or weeks, for example. The subjects ofadministration may be administered together, such as parts of a singlecomposition, for example, or otherwise. The subjects of administrationmay be administered substantially simultaneously (such as within lessthan or equal to about 5 minutes, about 3 minutes, or about 1 minute, ofone another, for example) or within a short time of one another (such aswithin less than or equal to about 1 hour, 30 minutes, or 10 minutes, orwithin more than about 5 minutes up to about 1 hour, of one another, forexample). The subjects of administration so administered may beconsidered to have been administered at substantially the same time. Oneof ordinary skill in the art will be able to determine appropriatedose(s) and time interval(s) for administration of subjects ofadministration to a subject body so that same will be present at morethan de minimus levels within the subject body and/or at effectiveconcentrations within the subject body. When the subjects ofadministration are concurrently administered to a subject body, any suchsubject of administration may be in an effective amount that is lessthan an effective amount that might be used were it administered alone.The term “effective amount,” which is further described herein,encompasses both this lesser effective amount and the usual effectiveamount, and indeed, any amount that is effective to elicit a particularcondition, effect, and/or response. As such, a dose of any such subjectof concurrent administration may be less than that which might be usedwere it administered alone. One or more effect(s) of any such subject(s)of administration may be additive or synergistic. Any such subject(s) ofadministration may be administered more than one time.

Generally, the term “effective amount” in reference to an active agentrefers to the amount of the active agent sufficient to elicit aparticular biological condition, effect, and/or response. The absoluteamount of a particular agent that is effective in this manner may varydepending on various factors, such as the desired biological endpoint,the agent itself, the subject or targeted part thereof, and/or the like,for example. An effective amount of an active agent may be administeredin a single dose or in multiple doses. Examples of a biologicalcondition, effect, or response that may result from an effective amountof an active agent include a maintaining and/or improving of a subject'sperformance of a task involving or associated with cognitive function, amaintaining and/or improving of a subject's performance in a test thatmeasures something relating to or associated with cognitive function, amaintaining and/or improving (slowing, for example) of a rate of declinein cognitive function, and/or the like, for example. A component may bedescribed herein as having at least an effective amount, or at least anamount effective, such as that associated with a particular goal orpurpose, such as any described herein.

Generally, the term “physiologically acceptable,” or “pharmaceuticallyacceptable,” means biologically or pharmacologically compatible for invivo use in animals or humans, e.g., approved by a regulatory agency ofthe Federal or a state government or listed in the U.S. Pharmacopeia orother generally recognized pharmacopeia for use in animals, and moreparticularly in humans.

As used herein, the term “treat”, in all its verb forms, included torelieve or alleviate at least one symptom of a disorder in a subject,the disorder including, e.g., pain, Alzheimer's disease, vasculardementia, or Parkinson's disease. The term “treat” may mean to relieveor alleviate the intensity and/or duration of a manifestation of adisorder experienced by a subject in response to a given stimulus (e.g.,pressure, tissue injury, cold temperature, etc.). For example, inrelation to dementia, the term “treat” may mean to relieve or alleviatecognitive impairment (such as impairment of memory and/or orientation)or impairment of global functioning (activities of daily living, ADL)and/or slow down or reverse the progressive deterioration in ADL orcognition. Within the meaning of the present invention, the term “treat”also denote to arrest, delay the onset (i.e., the period prior toclinical manifestation of a disease) and/or reduce the risk ofdeveloping or worsening a disease. The term “protect” is used herein tomean prevent delay or treat, or all, as appropriate, development orcontinuance or aggravation of a disease in a subject. Within the meaningof the present invention, the dementia is associated with a CNSdisorder, including without limitation neurodegenerative diseases suchas Alzheimer's disease (AD), Down's Syndrome and cerebrovasculardementia (VaD). The term “treatment” includes the act of “treating” asdefined above.

The term “dose proportional” as used herein refers to the relationshipbetween the dose of an active ingredient and its bioavailability. Forexample, dose proportionality exists if twice as much of the samecomposition will deliver twice the active ingredient and provide thesame bioavailability (e.g., AUC) as one dose of the dosage form. Thedose proportionality of the present invention applies to a wide range ofdoses as discussed in detail herein.

Generally, the term “elemental magnesium” as used in connection with amagnesium-counter ion compound described herein, may refer to a totalamount of magnesium that is present as free ion and magnesium that isbound with one or more counter ions. In general, such a term is not usedto refer to magnesium that may be associated with an agent other than amagnesium-counter ion compound that may be a component of amagnesium-counter ion composition (e.g., a pharmaceutical composition, adietary supplement composition, a foodstuff supplemented with amagnesium-counter ion compound). A small amount of magnesium may benaturally present in or otherwise associated with such an agent. Forexample, a fruit juice extract or flavoring agent may comprise an amountof magnesium from that naturally present in the fruit from which it wasderived. Generally, the term “elemental magnesium” as used in connectionwith an magnesium-counter ion compound would not encompass suchagent-associated magnesium.

As used herein, the terms “magnesium comprising component” (MCC) and“magnesium-counter ion compound” are used interchangeably, and they areuseful for purposes described herein, such as maintaining, enhancing,and/or improving health, nutrition, and/or another condition of asubject, such as magnesium deficiency, diabetes, mood, attention deficithyperactivity disorder, ALS, Parkinson's disease, anxiety, depressionand/or migraine, for example, and/or cognitive, learning, and/or memoryfunction, such as MCI and/or AD, for example.

Magnesium threonate has been shown to have the highest bioavailabilityin comparison to magnesium compounds commonly used as magnesiumsupplements. The ability to rapidly and efficiently deliver magnesiumfrom GI track to blood makes the compound an excellent candidate forpharmaceutical applications, such as treating neurological disorders ordeficiencies associated with magnesium deficit or those disorders forwhich magnesium is known to be effective. See U.S. patent applicationSer. No. 12/054,373, entitled “Magnesium Compositions, Methods of UsingSame, and Associated Technology.” For example, magnesium threonate wasfound to be effective as a memory enhancer in young animals and intreating memory loss associated with aging or Alzheimer's disease (AD)in animals. See U.S. patent application Ser. No. 12/054,373. However,for a composition to be useful as a dietary or nutritional supplement orfor enhancing health in general, it should have low side effects andprovide health benefits. Unlike a pharmaceutical composition, which maybe prescribed by a health professional to a patient with a specificmedical condition, a dietary or nutritional supplement may be taken byeither a healthy or unhealthy person and typically on a daily basis fora extended period of time, such as several months, several years or evena lifetime. Thus, it is important to provide sufficient data to supportthe long-term safety and benefit of a dietary/nutritional supplementwhen the supplement is administered at the effective dosage.

In some embodiments, the present invention provides a method ofsupplementing magnesium in a subject in need thereof. The subject can beany animal, as described herein. In some embodiments, said subject is ahuman. Immediate release formulations magnesium threonate (and relatedcompositions) have been show to be useful in a number of settings,including improved cognitive function and synaptic plasticity (U.S.patent application Ser. No. 12/054,367 entitled “Magnesium Compositionsand Uses Thereof for Cognitive Function” and Ser. No. 12/258,891entitled the same, treating neurological disorders (U.S. patentapplication Ser. No. 12/054,384 entitled “Magnesium Compositions andUses Thereof for Neurological Disorders”), metabolic disorders (U.S.patent application Ser. No. 12/054,374 entitled “Magnesium Compositionsand Uses Thereof for Metabolic Disorders”), and increasing lifespan(U.S. patent application Ser. No. 12/054,368, entitled “MagnesiumCompositions and Uses Thereof for Increasing Lifespan”).

The present invention provides methods to administer the oral dosageforms. In some embodiments, a method of administering an oral dosageform as described herein comprises administering the oral dosage formsto a subject once a day (UID), twice a day (BID), three times a day,four times a day, or more than six times a day. In some embodiments, theoral dosage forms as described herein are administered once a week,twice a week, three times a week, four times a week, five times a week,six times a week, or seven times a week. In some embodiments, the oraldosage forms as described herein are administered once a month, twice amonth, times a month, four times a month, five times a month, six timesa month, or more than six times a month.

The oral dosage forms as described herein can be used to supplementmagnesium in a continuous manner, e.g., over a lifetime. The dosageforms are also useful for providing magnesium over a period of time,e.g., for a period sufficient to treat, control or otherwise benefit amagnesium deficiency. In one embodiment, the present invention providesa method of supplementing magnesium in a subject in need thereof, themethod comprising administering an oral dosage form as described hereinto said subject at least twice a day for a period of 1 month or longer,2 months or longer, 3 months or longer, 4 months or longer, 5 months orlonger, 6 months or longer, or at least twice a day for a period of oneyear or longer. In some embodiments, once a day administration issufficient to provide optimal magnesium supplementation.

Using any regimen of administration, such as those described herein, thepresent invention provides method of treating a condition related tomagnesium deficiency comprising administering to a subject in needthereof any oral dosage form as described herein. For example, thecondition can be a neurological disorder, a cardiovascular disorder, ora metabolic disorder. Other conditions which benefit from the presentinvention include, but are not limited to, magnesium deficiency, mildcognitive impairment, Alzheimer's disease, attention deficithyperactivity disorder, ALS, Parkinson's disease, diabetes, migraine,anxiety disorder, mood disorder, and/or hypertension. One of skill inthe art will appreciate that the oral dosage forms and methods of thepresent invention can be use to treat any condition that respondsfavorably to magnesium supplementation.

In other embodiments, oral dosage forms of the present invention areadministered to a subject at a dose between about 4 mg elementalmagnesium/kg/day to about 8 mg elemental magnesium/kg/day, or betweenabout 2 mg elemental magnesium/kg/day to about 12 mg elementalmagnesium/kg/day, or between about 2 mg elemental magnesium/kg/day toabout 10 mg elemental magnesium/kg/day, or between about 4 mg elementalmagnesium/kg/day to about 12 mg elemental magnesium/kg/day, or betweenabout 6 mg elemental magnesium/kg/day to about 12 mg elementalmagnesium/kg/day, or between about 2 mg elemental magnesium/kg/day toabout 10 mg elemental magnesium/kg/day, or between about 4 mg elementalmagnesium/kg/day to about 10 mg elemental magnesium/kg/day, or betweenabout 6 mg elemental magnesium/kg/day to about 10 mg elementalmagnesium/kg/day. The optimal dosage can be dependent on the subject. Insome embodiments, the subject is a human. In such embodiment, the dosagecan be optimized to treat a condition in a human.

In some embodiments, the oral dosage forms of the present invention isadministered to a subject at a dose less than about 2 mg elementalmagnesium/kg/day, less than about 4 mg elemental magnesium/kg/day, lessthan about 6 mg elemental magnesium/kg/day, less than about 8 mgelemental magnesium/kg/day, less than about 10 mg elementalmagnesium/kg/day, or less than about 12 mg elemental magnesium/kg/day.In some embodiments, the oral dosage forms of the present invention areadministered to a subject at a dose more than about 2 mg elementalmagnesium/kg/day, more than about 4 mg elemental magnesium/kg/day, morethan about 6 mg elemental magnesium/kg/day, more than about 8 mgelemental magnesium/kg/day, more than about 10 mg elementalmagnesium/kg/day, or more than about 12 mg elemental magnesium/kg/day.The optimal dosage can depend on the subject. In some embodiments, thesubject is a human. In such an embodiment, the dosage can be optimizedto treat a condition in a human.

In some embodiments, the invention provides an oral dosage formcomprising magnesium (Mg) and threonate (T), wherein said threonatecomprises one or more of a threonate salt or a threonate precursor,wherein said oral dosage form is readily absorbed or retained uponadministering to a subject such that at least about 50% of saidadministered magnesium is absorbed in said subject, or that at least 30%of the magnesium administered to the subject is retained over a periodof at least two days when said oral dosage form is administered at adose of 20 mg/kg/day or higher.

The forms of magnesium described herein are advantageous for their highbioavailability. The schedule of administration and dose ofadministration can depend on the amount of magnesium that isbioavailable in a subject. In some embodiments, more than about 10%,20%, 30%, 40%, 50%, 60%, 70%, 80% or more than about 90% of saidadministered magnesium is absorbed in said subject.

In some embodiments, the amount of magnesium absorbed in the subject isproportional to dosage. For example, the amount of magnesium absorbedcan be linearly proportional to the dosage. In some embodiments, theoral dosage form exhibits a dose-proportional increase in absorbedmagnesium when administered to a subject in an amount between about 20mg/kg/day and about 100 mg/kg/day, between about 20 mg/kg/day and about90 mg/kg/day, or between about 20 mg/kg/day and about 80 mg/kg/day, orbetween about 20 mg/kg/day and about 70 mg/kg/day, or between about 20mg/kg/day and about 60 mg/kg/day, or between about 20 mg/kg/day andabout 50 mg/kg/day, or between about 30 mg/kg/day and about 100mg/kg/day, or between about 40 mg/kg/day and about 100 mg/kg/day, orbetween about 50 mg/kg/day and about 100 mg/kg/day, or between about 60mg/kg/day and about 100 mg/kg/day, or between about 70 mg/kg/day andabout 100 mg/kg/day.

In some embodiments, the dosage form of the present invention has adissolution rate of magnesium about 40-80% within about 6 to 10 hours.

Magnesium compositions have the potential to cause diarrhea. Indeed,magnesium compounds have been commonly used as laxatives, andmagnesium-hydroxide is a commonly known over-the-counter laxative and isthe active ingredient in Phillips' Milk of Magnesia. Moreover, ChinesePatent 1200366A discloses that magnesium threonate is useful as alaxative. However, the present invention shows that magnesium threonatehas the least tendency to cause diarrhea among a number of commonly usedmagnesium supplement compounds. See I.Example 2 and FIG. 1.

The incidence of diarrhea can be estimated by providing a dosage ofmagnesium threonate or a precursor thereof to a group of test animals,e.g., rat or mice, and assessing the incidence of diarrhea in the groupof animals. In one embodiment, the present invention provides an oraldosage form comprising between about 30 mg to 2000 mg magnesium (Mg),wherein said oral dosage form is a controlled release formulation, andwherein upon administering said oral dosage form to a subject a dosageof greater than 40 mg/day yields an incidence of diarrhea of less than20%. The incidence can depend on the particular subject, the body weightof the subject, and the bioavailability of the magnesium provided. Forexample, the incidence of diarrhea in mice fed a water solutioncontaining magnesium threonate can depend on, e.g., the strain, age orsex of the mice.

In some embodiments, the oral dosage forms of the present inventionprovides for an incidence of diarrhea of less than 50%, 40%, 30%, 20%,10%, or less than about 5% when administered to at a dosage of greaterthan 80 mg/day.

In some embodiments, the incidence of diarrhea is less than 20% whenadministered to a subject at a dosage of greater than 40 mg/day for atleast about 2, 3, 4, 5, 6 days. In some embodiments, the incidence ofdiarrhea is less than 20% when administered to a subject at a dosage ofgreater than 40 mg/day for at least about one week, or two weeks, orthree weeks or more. In some embodiments, the incidence of diarrhea isless than 20% when administered to a subject at a dosage of greater than40 mg/day for at least about one month.

The high bioavailability of magnesium threonate compared to other formsof magnesium is shown in FIGS. 2A and B. For example, magnesium oxide,the most widely available magnesium supplement, has been reported tohave a bioavailability of only 4% (Ranade V V, Somberg J C.Bioavailability and pharmacokinetics of magnesium after administrationof magnesium salts to humans. Am J Ther. 2001 September-October;8:345-57). Thus, taking a similarly recommended amount of elementalmagnesium using magnesium threonate in long-term may expose a subject toa much higher blood magnesium level previously unattainable with othermagnesium supplements. Magnesium threonate also provides superiormagnesium retention in the body. FIGS. 2C and D show that, althoughmagnesium threonate has the highest magnesium absorption rate, its rateof blood magnesium excretion through urine is similar to other magnesiumcompounds. As a result, the rate of magnesium retention (absorptionrate−excretion rate), which measures the ultimate bioavailability of amagnesium compound, is higher for magnesium threonate than for othermagnesium compounds. Accordingly, this makes magnesium threonate by farthe most efficient compound to elevate magnesium levels in tissues andother body fluids. Indeed, magnesium threonate increased brain magnesiumlevel (i.e., magnesium concentration in cerebral spinal fluid (CSF))significantly in mice following 24 days of treatment, whereas magnesiumchloride and magnesium gluconate in milk had relatively limited effect(FIG. 3). These data indicate that threonate is unusually capable offacilitating magnesium to enter the brain. This rise of brain magnesiumcoincided with the animals' cognitive function improvement. See U.S.patent application Ser. No. 12/054,373, entitled “MagnesiumCompositions, Methods of Using Same, and Associated Technology.”

Accordingly, the present invention provides a method of elevatingmagnesium in a central nervous system of a subject comprisingadministering to said subject an oral dosage form as described herein.In some embodiments, the oral dosage form comprises a controlled-releaseform of magnesium (Mg) and threonate (T), wherein said threonatecomprises one or more of a threonate salt or a threonate precursor. Insome embodiments, administering the oral dosage form provides anincreased concentration of magnesium in a cerebral spinal fluid of thesubject, wherein said increased concentration of magnesium in saidcerebral spinal fluid of the subject ranges between about a 5% increaseto about a 10% increase after about 10 days compared to baseline in theabsence of administering magnesium. In some embodiments, the increasedconcentration of magnesium in said cerebral spinal fluid ranges betweenabout a 1% to about a 10% increase, or about a 2% to about a 10%increase, or about a 3% to about a 10% increase, or about a 4% increaseto about a 10% increase after about 10 days administering said oraldosage form. In some embodiments, said increased concentration ofmagnesium in said cerebral spinal fluid of the subject is increased bymore than about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or more than about a10% increase after about 10 days.

The compositions of the present invention are able to provide such highlevels of magnesium without adverse effect. In some embodiments, thecompositions are provided with adverse effect for at least 1 month, 2months, 3 months, 4 months, 5 months, or for at least 6 months. In someembodiments, the compositions are provided with adverse effect for atleast 1 year, or 2 years, or 5 years, or 20 years, or 20 years, or for alifetime. For example, normal male and female mice at age 15 months weretreated with magnesium threonate for their remaining entire lifespan.See I.Example 4. The results show that the magnesium-treated animals hadnormal lifespan (FIG. 4). In these experiments, the amount of magnesiumdaily dosage (75 mg/kg/day) corresponded to the effective dosage formemory enhancement in normal young and aging mice as well as in AD micein the short-term magnesium treatment experiments. See U.S. patentapplication Ser. No. 12/054,373, “Magnesium Compositions, Methods ofUsing Same, and Associated Technology.” The data indicate that magnesiumthreonate has no long-term toxicity in animals when used at aphysiologically effective dosage.

The oral dosage forms of the present invention further provideprotective health benefits against a high calorie diet. In anexperiment, the compound was given to 10-month old mice on a highcalorie diet throughout the remaining lifespan. As expected, the groupof animals under high calorie diet plus magnesium threonate and anothergroup of animals under high calorie diet but without magnesium threonate(control group #1) both gained significant weight over time (FIG. 5A).Also as expected, the animals in the high calorie control group (controlgroup #1) died at a much higher rate than animals fed standard mousediet (control group #2) (FIG. 5B). However, the animals under highcalorie diet plus magnesium threonate had lifespan similar to that ofthe animals under standard diet. It is generally well-known that a highcalorie diet may lead to obesity, which in turn can lead to a variety ofhealth problems including diabetes and cardiovascular diseases. Theresults in FIG. 5 suggest that magnesium threonate may have preventativeeffect to metabolic syndrome and other health problems associated withobesity, thus making the compound useful for general health-enhancingpurpose in addition to its use as a magnesium supplement.

A number of serious complications can result from obesity. These includetype II diabetes, unhealthy cholesterol levels, heart disease (e.g.,atherosclerosis, myocardial infarction, congestive heart failure,thromboembolism, sudden cardiac death, angina or chest pain), stroke,high blood pressure, sleep apnea, breathing disorders, musculoskeletaldisorders (e.g., osteoarthritis, back pain), gall bladder disease, fattyliver disease, cancer, asthma, chronic headaches, varicose veins, deepvein thrombosis, coronary artery disease, gastroesophageal refluxdisease (GERD), heartburn, depression, hernias, gall stones, urinaryincontinence, menstrual irregularity, infertility, and increasedpregnancy risk for both mother and child. Obesity leads to numerouspremature deaths.

In one embodiment, the present invention provides a method ofmaintaining a high calorie diet without a substantial risk of highcalorie related adverse effect, comprising administering an oral dosageform as described herein to a subject. In one embodiment, the oraldosage form comprises magnesium (Mg) and threonate (T), wherein thethreonate comprises one or more of a threonate salt or a threonateprecursor. The oral dosage form is effective in increasing the life spanof a subject on a high calorie diet. In some embodiments, administeringsaid oral dosage form to a subject on a high calorie diet yields aprotective effect such that said subject's life span is comparable to anaverage life span of a subject having a median weight.

In one embodiment, the invention provides an oral dosage form comprisingmagnesium (Mg) and threonate (T), wherein said threonate comprises oneor more of a threonate salt or a threonate precursor, whereinadministering said oral dosage form to a subject provides protectionagainst adverse effects of a high calorie diet in said subject. Adverseeffects include, but are not limited to, artherosclerosis, heartdisease, myocardial infarction, stroke, thromboembolism, metabolicsyndrome, and diabetes. A variety of other complications resulting fromobesity are disclosed herein.

The health beneficial effects of the compounds of the present inventioncan be measured in test animals, e.g., rodents, e.g., mice or rats. SeeI.Example 5. In some embodiments, the oral dosage form increasessurvival rate by at least about 10%, 20%, 30%, 40%, 50%, or more than50% in such animals who are on a high calorie diet for at least about 60weeks. In some embodiments, the increased survival rate is observableover shorter time periods. In some embodiments, the oral dosage formincreases survival rate by a statistically significant amount in suchanimals who are on a high calorie diet for at least about 10 weeks, 20weeks, 30 weeks, 40 weeks, or for at least about 50 weeks. One of skillin the art will appreciate how to measure survival effects, e.g., usinga Kaplan-Meier survival curve analysis.

III. Kits

The present invention also provides kids that can be used to practicethe present invention. A kit may comprise at least one component of anymagnesium-counter ion composition described herein or anymagnesium-counter ion composition described herein. In some embodiments,a kit comprises magnesium-threonate supplements, or any of thevariations described herein, in a controlled-release oral dosage form.In some embodiments, a kit contains a bottle or other holder containingsaid oral dosage form. In some embodiments, the oral dosage forms arecomprised in blister packs to simplify health and therapeutic regimenfor end users.

EXAMPLES Example 1 Methods

Animals: Adult male Sprague-Dawley rats were obtained from Wei Tong LiHua Beijing, China. Rats were individually-housed with free access tostandard food and water under a 12:12 h reversed light-dark cycle, withlight onset at 8:00 p.m. On arrival and before the start of thebioavailability experiments (see below), rats were fed a commercialpelleted diet, containing normal magnesium (0.15%) and tap water ad lib.All experimental procedures were approved by the Tsinghua UniversityCommittees on Animal Care.

Treatment with Different Magnesium Preparations:

The following magnesium preparations were used in the present study,Magnesium threonate (Magceutics Inc., USA), Magnesium chloride andglycinate (Modern Eastern Fine Chemical, China), magnesium gluconate andcitrate (Sigma-Aldrich, Germany). Lactose was obtained from Biobasic Inc(Beijing, China). In order to supply animals with a dose of 50 mg/kg/dayelemental magnesium the following doses of each preparation weredissolved in the daily drinking volume: magnesium threonate (606mg/kg/day), magnesium chloride (196 mg/kg/day), magnesium gluconate (853mg/kg/day), magnesium citrate (310 mg/kg/day), and magnesium glycinate(355 mg/kg/day).

Determination of Magnesium Absorption, Excretion and Retention:

Rats were individually-housed in metabolic cages for 12 days, duringwhich time the animals received magnesium-free food. On day 4 throughday 10, animals received de-ionized water containing one of the testedmagnesium compounds. From day 11 through day 12, the rats were fed withmagnesium-free food and de-ionized water. Urine from each rat wascollected daily during the magnesium supplement period (days 4 to 10),and fecal pellets were collected from day 5 to day 10. The collectedurine and fecal pellets were pooled and the total volume of the pooledurine and total weight of feces from each rat were recorded. The pooledurine and fecal pellets from each rat were analyzed for magnesiumcontent using an inductively coupled plasma-atomic emission spectrometer(ICP-AES), and the total magnesium content (milligrams) in urine andfeces was determined.

The percentages of absorption, excretion, and retention were estimatedby the slope of the linear regression fit using the following equations:absorption=(Mg_(intake)−Mg_(feces))*100%/Mg_(intake)  (Equation 1)excretion=Mg_(urine)*100%/(Mg_(intake)−Mg_(feces))  (Equation 2)retention=(Mg_(intake)−Mg_(feces)−Mg_(urine))*100%/Mg_(intake)  (Equation3)

Margin of Safety of Different Magnesium Preparations:

To evaluate the laxative properties of different magnesium preparations,animals were divided into groups of 10. Each group received thespecified magnesium preparation via drinking water at a dose rangingfrom 15 to 138 mg/kg/day elemental magnesium. The magnesium dosedissolved in the daily intake volume of water was determined based onintake of ˜30 ml/day/rat. Animals were supplied with the magnesiumsupplemented drinking water for 4 days, after which time the number ofanimals that developed diarrhea was monitored and calculated as apercentage of the total number of animals in the respective group.

Magnesium Content in the Cerebrospinal Fluid:

In a separate group of animals, the content of magnesium ion incerebrospinal fluid (CSF) was estimated at baseline (day 0), and at 12and 24 days of treatment with different magnesium preparations. Animalswere treated with different magnesium preparations via drinking water ata dose of approximately 50 mg/kg/day elemental magnesium. Before eachsampling point, rats were anesthetized with Chloral hydrate (400 mg/kg,i.p.) and 50 μl/animal CSF was manually obtained from the cisterna magnaby the interruption of the atlanto-occipital membrane using amicro-needle having a 450 μm diameter. The CSF samples were collectedand stored at −20° C. until the magnesium measurements were performed.Magnesium levels were determined as described above.

Statistical Analysis:

All data were approximated with a normal distribution. Bioavailabilityanalyses were performed using linear regression with 95%confidence-interval. To determine the toxic dose for 50% of the animals(TD50), non-linear regression best-fit with variable Hill-slope analyseswas used with a confidence interval of 95%. One-way analysis of variancewas used to analyze the cerebrospinal fluid data. GraphPad prism wasused for data analysis (version 5.00, GraphPad software Inc.). P-valuesless than 0.05 were considered significant.

Example 2 Effect of Magnesium Supplementation on the Incidence ofDiarrhea

FIG. 1 shows the incidence of diarrhea in rats fed a variety ofmagnesium supplements. As the magnesium dose was increased, thepercentage of animals that developed diarrhea increased proportionally.At higher doses, magnesium threonate (MgT) was less likely to inducediarrhea. TD50 (toxic dose required to induce diarrhea in 50% ofanimals) of each compound was as follow: magnesium threonate: 131.5mg/kg/day; magnesium gluconate in milk (MgG+milk): 119.1 mg/kg/day;magnesium gluconate (MgG): 99.7 mg/kg/day; magnesium chloride (MgCl2):90.0 mg/kg/day. Magnesium compounds were added to the rats drinkingwater, thereby mimicking slow release of Magnesium compounds as the ratsdrink over time.

Example 3 Elevation of Magnesium Concentration in Cerebrospinal Fluid([Mg²⁺]CSF)

Magnesium chloride (MgCl₂), magnesium gluconate in milk (MgG+milk), andmagnesium threonate (MgT) were fed to mice for 24 days. FIG. 3 shows theelevation of magnesium concentration in cerebrospinal fluid ([Mg²⁺]CSF)following treatment with the different magnesium preparations. Magnesiumthreonate increased magnesium concentration in cerebral spinal fluidsignificantly in mice following 24 days of treatment, whereas magnesiumchloride and magnesium gluconate in milk had relatively limited effect.The data were significant at day 24 using a one-way ANOVA (p<0.05).

Example 4 Effect of Magnesium Threonate (MgT) on the Lifespan of AnimalsFed Normal Food

Male and female mice at 10 months of age were purchased from the VitalRiver Laboratory Animal Technology Co. Ltd Beijing, China. The mice werefed a commercial pelleted diet (Shanghai SLAC Laboratory Animal Co.Ltd), containing normal magnesium (0.15%) and tap water ad lib for 5months prior to the start of the experiment. Four female mice werehoused together in single cage with free access to food and water undera 12:12 h light-dark cycle, with light onset at 8:00 a.m. Male mice werehoused individually. At the start of the experiment, magnesium threonate(75 mg/kg/day elemental magnesium) was added to drinking water for miceas indicated. Survival curves were plotted using the Kaplan-Meiermethod, which includes all available animals at each time point. 30 micewere used in each group at the start of experiments (FIGS. 4A and B).

Example 5 Effect of Magnesium Threonate (MgT) on the Lifespan of AnimalsFed a High Calorie Diet

Female mice at 9 months of age were purchased from the Vital RiverLaboratory Animal Technology Co. Ltd Beijing, China. The mice were fedon a commercial pelleted diet (Shanghai SLAC Laboratory Animal Co. Ltd),containing normal magnesium (0.15%) and tap water ad lib for one monthprior to the start of the experiment. Four mice were housed together insingle cage with free access to food and water under a 12:12 hlight-dark cycle, with light onset at 8:00 a.m. At the start ofexperiment, a portion of the mice were switched to a high-calorie (HC)diet by the addition of hydrogenated coconut oil to provide 60% ofcalories from fat (Baur et al., 2006 Resveratrol improves health andsurvival of mice on a high-calorie diet. Nature 444, 337-342). A portionof the HC-fed mice were supplemented with MgT supplement via theirdrinking water at approximately 45 mg/kg/day elemental magnesium. Foodintake and body weight were measured on a weekly basis for the durationof the study. Survival curves were plotted using the Kaplan-Meiermethod, which includes all available animals at each time point. 60 micewere used in each group (i.e., normal diet, HC diet, HC diet with MgTsupplementation) at the start of experiments (FIGS. 5A and B).

Example 6 Preparation and Release Profile of Controlled-Release Tablets

To prepare controlled release tablets, magnesium threonate waspulverized and screen filtered using 80 mesh sieves. The magnesiumthreonate powder was mixed with 15% polyvinylpyrrolidone (PVP) in 95%ethanol at 0.3 mL for each gram of magnesium threonate powder. Theresulting particles were screen filtered to remove any un-boundmagnesium threonate using 12-mesh sieves. The particles were dried withforced air at 65° C. for 15 minutes, followed by screen filtration againto remove any unbound debris using 12-mesh sieves. A pharmaceuticallyacceptable amount of magnesium stearate was added to the dried particlesas a lubricant (˜5 mg for each gram of magnesium threonate). Afterthorough mixing, the lubricated particles were compressed into tabletsof ˜1 g in size. A coating liquid was prepared by mixing 223.67 g of 30%SR 30D (polyvinyl acetate) in water, 6.7 g of propylene glycol and 19 gof PVP, followed by adding water to a total weight of 450 g. Apharmaceutically suitable amount of a lake dye and talc powder ortitanium oxide were also added to provide protection from light andfacilitate the coating process. The resulting mixture was well stirredto form a homogeneous suspension. The tablets were coated at 45-55° C.using the above coating liquid, resulting in controlled-release tabletseach comprising ˜1 g of magnesium threonate and 70-90 mg of additives.

The release profile of the controlled-release tablets prepared above wasexamined in 250 mL normal saline at 37° C. at a stirring rate of 75 rpm.The amount of released magnesium over time was measured using aspectroscopic method (Raymond J. Liedtke and Gery Kroon Clin. Chem.30(11), 1801-1804 (1984)). The release profile is shown in Table 1.

TABLE 1 Released magnesium over time Time (h) % of released magnesium 20 4 6.9 6 32.5 8 60.1 10 76.2 12 83.3 24 104.6

The above data is plotted in FIG. 6B.

While preferred embodiments of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the invention. It should be understoodthat various alternatives to the embodiments of the invention describedherein may be employed in practicing the invention. It is intended thatthe following claims define the scope of the invention and that methodsand structures within the scope of these claims and their equivalents becovered thereby.

What is claimed is:
 1. A method of supplementing magnesium in a subjectin need thereof, comprising administering an oral dosage form comprisingmagnesium (Mg) and threonate (T), wherein at least a portion of themagnesium and threonate are complexed in a salt form of MgT₂, andfurther wherein the oral dosage form is a controlled releaseformulation.
 2. The method of claim 1, wherein the oral dose isadministered to treat a magnesium deficient condition.
 3. The method ofclaim 2 wherein the magnesium deficient condition is selected from thegroup consisting of a neurological disorder, a cardiovascular disorder,and a metabolic disorder.
 4. The method of claim 1, wherein the oraldose is administered to elevate magnesium in a central nervous system ofa subject in need thereof.
 5. The method of claim 1, wherein the subjectadopts a high calorie diet.
 6. The method of claim 1, wherein the oraldosage form is administered to said subject at least twice a day for aperiod of 1 month or longer.
 7. The method of claim 1, wherein the oraldosage form has an in vitro dissolution profile in a dissolution medium;and further wherein the dissolution profile ranges between less than orequal to 5% in about 2 hours, less than 10% in about 4 hours, less than40% in about 6 hours, greater than or equal to 60% in about 10 hours,and greater than or equal to 80% in about 12 hours as measured using aUSP type II paddle dissolution system at 75 rpm, at a temperature of 37°C.
 8. The method of claim 1, wherein the oral dosage form has an invitro dissolution profile in a dissolution medium; and further whereinthe dissolution profile ranges between less than 5% in about 2 hours,less than 10% in about 4 hours, less than 40% in about 6 hours, greaterthan or equal to 60% in about 10 hours, and greater than or equal to 80%in about 12 hours as measured using a USP type II paddle dissolutionsystem at 75 rpm, at a temperature of 37° C.
 9. The method of claim 1,wherein the oral dosage form comprises between about 10 mg to 500 mgelemental magnesium (Mg), and further wherein administering the oraldosage form to a Sprague-Dawley rat at a dosage of about 75 mg/kg/dayyields an incidence of diarrhea of less than 20%.
 10. The method ofclaim 1, wherein upon administering the oral dosage form to a subject atleast 50% of the administered magnesium is absorbed in the subject, orthat at least 30% of the magnesium administered to the subject isretained by the subject over a period of at least two days when the oraldosage form is administered at a dose of 20 mg/kg/day or higher.
 11. Themethod of claim 1, wherein the oral dosage form is administered to thesubject in an amount effective to reduce the subject's risk of adverseeffects of a high calorie diet relative to the subject's risk beforetreatment, wherein the adverse effect is atherosclerosis, heart disease,myocardial infarction, stroke, thromboembolism, metabolic syndrome, ordiabetes.
 12. The method of claim 1, wherein the magnesium and threonatein the oral dosage form is encapsulated in a tablet.
 13. The method ofclaim 1, wherein elemental magnesium (Mg) is present in an amount equalto at least 10 mg by weight of the oral dosage form.
 14. The method ofclaim 1, wherein elemental magnesium (Mg) is present in an amount equalto at least 20 mg by weight of the oral dosage form.
 15. The method ofclaim 1, wherein said magnesium (Mg) is present in an amount greaterthan about 1% by weight of the oral dosage form.
 16. The method of claim1, wherein the oral dosage form further comprises a metal ion selectedfrom the group consisting of calcium, potassium, sodium, chromium, iron,selenium, zinc, manganese, molybdenum, vanadium, and lithium.
 17. Themethod of claim 1, wherein the oral dosage form further comprises one ormore antioxidants selected from the group consisting of resveratrol,ellagic acid, quercetin, lipoic acid, and vitamin C.
 18. The method ofclaim 1, wherein the oral dosage form further comprises a polymer bindermixed with the magnesium (Mg) and threonate (T).
 19. The method of claim1, wherein the oral dosage form is administered to a human subject at adose between about 1 mg elemental magnesium/kg/day to about 16 mgelemental magnesium/kg/day.